Informing patients of a dire diagnosis — or even one that will require significant lifestyle changes — is never easy. But what’s even more challenging is when patients don’t accept their medical condition or a future that might include a difficult treatment protocol or even new medications or surgery.

“This is a challenging space to be in because this isn’t an exact science,” said Jack Jacoub, MD, medical director of MemorialCare Cancer Institute at Orange Coast Memorial in Fountain Valley, California. “There’s no formal training to deal with this — experience is your best teacher.”

Ultimately, helping a person reconceptualize what their future looks like is at the heart of every one of these conversations, said Sourav Sengupta, MD, MPH, associate professor of psychiatry and pediatrics at the Jacobs School of Medicine and Biomedical Sciences at the University at Buffalo, Buffalo, New York. “As physicians, we’re charged with helping our patients navigate a difficult and challenging time in their life,” he told this news organization.

“It’s not infrequent that patients are struggling to rethink what it will be like to be a person with an illness that might be chronic and how this will change their life,” he said.

And because denial is commonly the initial way a patient might cope with absorbing news that’s hard to hear, you’ll need to be extremely patient and empathetic.

“The goal is to build trust with this person, including trust in you, the hospital itself, and the entire team treating the patient,” Dr. Jacoub said.

“A diagnosis, especially in my field of oncology, can be scary. Spending time explaining their prognosis is very important. This can’t be a rushed scenario.”

More advice on helping patients who are in denial about their medical condition:
 

Make Sure They Understand What’s Going on

In cardiology, it’s common for patients to be hospitalized when they first learn that they have a disease they must manage for the rest of their life, said Stephanie Saucier, MD, a noninvasive cardiologist and codirector of the Women’s Heart Wellness Program at Hartford Healthcare’s Heart and Vascular Institute.

“Especially after someone has had a heart attack, a stroke, or they had bypass or stents placed, I like to see what their understanding of the disease is,” Dr. Saucier said. “I ask them, ‘What do you understand about what happened to you’. It can get confusing when you’re in the hospital and are told a lot of information in a short period of time.”
 

Share the Data

If a patient remains resistant to the news of a diagnosis, sharing test results can be beneficial. “I’ll often say, ‘here are the scans; this is the path report; this is the bloodwork; this is your biopsy report; these are the things we have’,” Dr. Jacoub said.

“Yes, this is clinical, but it helps to communicate the information you have and do it with data. For example, I might add, ‘Would you like to see some of the things [results, scans, tests] we’re talking about today?’ This also helps establish trust.”
 

Help Them Wrap Their Mind Around a Lifelong Condition

It’s often challenging for patients to accept that what they think is a one-time health issue will affect them for a lifetime. “I use juvenile diabetes as a way to explain this,” Dr. Saucier said. “I ask them what they would do if, say, their child was diagnosed with juvenile diabetes.”

Of course, patients agree that they wouldn’t give a child insulin for only a brief period. They understand that the condition must be treated in the long term. This kind of analogy can help patients understand that they, too, have a disorder requiring lifelong treatment.
 

Be Ready to Respond

Dr. Sengupta says that it’s important to be prepared with an answer if your patient is challenging or suggests that the diagnosis is fake or that you don’t have their best interests in mind.

“It’s understandable that patients might feel frustrated and upset,” he said. “It’s challenging when somehow a patient doesn’t assume my best intent.”

They might say something like, “You’re trying to make more money” or “you’re a shill for a pharma company.” In that case, you must listen. Patiently explain, “I’m your doctor; I work for you; I’m most interested in you feeling healthy and well.”

Occasionally, you’ll need a thick skin when it comes to inaccurate, controversial, or conspiratorial conversations with patients.
 

Acknowledge Differences

News of an illness may clash with a person’s take on the world. “A cancer diagnosis, for example, may clash with religious beliefs or faith-based ideology about the healthcare system,” said Aaron Fletcher, MD, a board-certified otolaryngologist specializing in head and neck surgery at the Georgia Center for Ear, Nose, Throat, and Facial Plastic Surgery in Atlanta, Georgia.

“If you have a patient who is coming to you with these beliefs, you need to have a lot of empathy, patience, and good communication skills. It’s up to you to break through the initial doubt and do your best to explain things in layman’s terms.”
 

Find Mutual Ground

If your patient still denies their health issues, try to find one thing you can agree on regarding a long-term game plan. “I’ll say, ‘Can we at least agree to discuss this with other family members or people who care about you’?” Dr. Jacoub said.

“I always tell patients that loved ones are welcome to call me so long as they [the patient] give permission. Sometimes, this is all that it takes to get them to accept their health situation.”
 

Seven Ways to Cope With Diagnosis  Denial

This news organization asked David Cutler, MD, a board-certified family medicine physician at Providence Saint John›s Health Center in Santa Monica, California, for tips in helping patients who are having a challenging time accepting their condition:

• Listen Actively. Allow the patient to express their feelings and concerns without judgment. Active listening can help them feel heard and understood, which may open the door to discussing their condition more openly.
• Provide Information. Offer factual information about their medical condition, treatment options, and the potential consequences of denial. Provide resources such as pamphlets, websites, or books that they can review at their own pace.
• Encourage Professional Help. You may want to suggest that your patient seek professional help from a therapist, counselor, or support group. A mental health professional can assist patients in processing their emotions and addressing their denial constructively.
• Involve Trusted Individuals. Enlist the support of trusted friends, family members, or healthcare professionals who can help reinforce the importance of facing their medical condition.
• Respect Autonomy. While it’s essential to encourage the person to accept their diagnosis, ultimately, the decision to get treatment lies with them. Respect their autonomy and avoid pushing them too hard, which could lead to resistance or further denial.
• Be Patient and Persistent. Overcoming denial is often a gradual process. Be patient and persistent in supporting the person, even if progress seems slow.
• Set Boundaries. It’s essential to set boundaries to protect your well-being. While you can offer support and encouragement, you cannot force someone to accept their medical condition. Recognize when your efforts are not being productive and take care of yourself in the process.

A version of this article first appeared on Medscape.com.

Informing patients of a dire diagnosis — or even one that will require significant lifestyle changes — is never easy. But what’s even more challenging is when patients don’t accept their medical condition or a future that might include a difficult treatment protocol or even new medications or surgery.

“This is a challenging space to be in because this isn’t an exact science,” said Jack Jacoub, MD, medical director of MemorialCare Cancer Institute at Orange Coast Memorial in Fountain Valley, California. “There’s no formal training to deal with this — experience is your best teacher.”

Ultimately, helping a person reconceptualize what their future looks like is at the heart of every one of these conversations, said Sourav Sengupta, MD, MPH, associate professor of psychiatry and pediatrics at the Jacobs School of Medicine and Biomedical Sciences at the University at Buffalo, Buffalo, New York. “As physicians, we’re charged with helping our patients navigate a difficult and challenging time in their life,” he told this news organization.

“It’s not infrequent that patients are struggling to rethink what it will be like to be a person with an illness that might be chronic and how this will change their life,” he said.

And because denial is commonly the initial way a patient might cope with absorbing news that’s hard to hear, you’ll need to be extremely patient and empathetic.

“The goal is to build trust with this person, including trust in you, the hospital itself, and the entire team treating the patient,” Dr. Jacoub said.

“A diagnosis, especially in my field of oncology, can be scary. Spending time explaining their prognosis is very important. This can’t be a rushed scenario.”

More advice on helping patients who are in denial about their medical condition:
 

Make Sure They Understand What’s Going on

In cardiology, it’s common for patients to be hospitalized when they first learn that they have a disease they must manage for the rest of their life, said Stephanie Saucier, MD, a noninvasive cardiologist and codirector of the Women’s Heart Wellness Program at Hartford Healthcare’s Heart and Vascular Institute.

“Especially after someone has had a heart attack, a stroke, or they had bypass or stents placed, I like to see what their understanding of the disease is,” Dr. Saucier said. “I ask them, ‘What do you understand about what happened to you’. It can get confusing when you’re in the hospital and are told a lot of information in a short period of time.”
 

Share the Data

If a patient remains resistant to the news of a diagnosis, sharing test results can be beneficial. “I’ll often say, ‘here are the scans; this is the path report; this is the bloodwork; this is your biopsy report; these are the things we have’,” Dr. Jacoub said.

“Yes, this is clinical, but it helps to communicate the information you have and do it with data. For example, I might add, ‘Would you like to see some of the things [results, scans, tests] we’re talking about today?’ This also helps establish trust.”
 

Help Them Wrap Their Mind Around a Lifelong Condition

It’s often challenging for patients to accept that what they think is a one-time health issue will affect them for a lifetime. “I use juvenile diabetes as a way to explain this,” Dr. Saucier said. “I ask them what they would do if, say, their child was diagnosed with juvenile diabetes.”

Of course, patients agree that they wouldn’t give a child insulin for only a brief period. They understand that the condition must be treated in the long term. This kind of analogy can help patients understand that they, too, have a disorder requiring lifelong treatment.
 

Be Ready to Respond

Dr. Sengupta says that it’s important to be prepared with an answer if your patient is challenging or suggests that the diagnosis is fake or that you don’t have their best interests in mind.

“It’s understandable that patients might feel frustrated and upset,” he said. “It’s challenging when somehow a patient doesn’t assume my best intent.”

They might say something like, “You’re trying to make more money” or “you’re a shill for a pharma company.” In that case, you must listen. Patiently explain, “I’m your doctor; I work for you; I’m most interested in you feeling healthy and well.”

Occasionally, you’ll need a thick skin when it comes to inaccurate, controversial, or conspiratorial conversations with patients.
 

Acknowledge Differences

News of an illness may clash with a person’s take on the world. “A cancer diagnosis, for example, may clash with religious beliefs or faith-based ideology about the healthcare system,” said Aaron Fletcher, MD, a board-certified otolaryngologist specializing in head and neck surgery at the Georgia Center for Ear, Nose, Throat, and Facial Plastic Surgery in Atlanta, Georgia.

“If you have a patient who is coming to you with these beliefs, you need to have a lot of empathy, patience, and good communication skills. It’s up to you to break through the initial doubt and do your best to explain things in layman’s terms.”
 

Find Mutual Ground

If your patient still denies their health issues, try to find one thing you can agree on regarding a long-term game plan. “I’ll say, ‘Can we at least agree to discuss this with other family members or people who care about you’?” Dr. Jacoub said.

“I always tell patients that loved ones are welcome to call me so long as they [the patient] give permission. Sometimes, this is all that it takes to get them to accept their health situation.”
 

Seven Ways to Cope With Diagnosis  Denial

This news organization asked David Cutler, MD, a board-certified family medicine physician at Providence Saint John›s Health Center in Santa Monica, California, for tips in helping patients who are having a challenging time accepting their condition:

• Listen Actively. Allow the patient to express their feelings and concerns without judgment. Active listening can help them feel heard and understood, which may open the door to discussing their condition more openly.
• Provide Information. Offer factual information about their medical condition, treatment options, and the potential consequences of denial. Provide resources such as pamphlets, websites, or books that they can review at their own pace.
• Encourage Professional Help. You may want to suggest that your patient seek professional help from a therapist, counselor, or support group. A mental health professional can assist patients in processing their emotions and addressing their denial constructively.
• Involve Trusted Individuals. Enlist the support of trusted friends, family members, or healthcare professionals who can help reinforce the importance of facing their medical condition.
• Respect Autonomy. While it’s essential to encourage the person to accept their diagnosis, ultimately, the decision to get treatment lies with them. Respect their autonomy and avoid pushing them too hard, which could lead to resistance or further denial.
• Be Patient and Persistent. Overcoming denial is often a gradual process. Be patient and persistent in supporting the person, even if progress seems slow.
• Set Boundaries. It’s essential to set boundaries to protect your well-being. While you can offer support and encouragement, you cannot force someone to accept their medical condition. Recognize when your efforts are not being productive and take care of yourself in the process.

A version of this article first appeared on Medscape.com.

Informing patients of a dire diagnosis — or even one that will require significant lifestyle changes — is never easy. But what’s even more challenging is when patients don’t accept their medical condition or a future that might include a difficult treatment protocol or even new medications or surgery.

“This is a challenging space to be in because this isn’t an exact science,” said Jack Jacoub, MD, medical director of MemorialCare Cancer Institute at Orange Coast Memorial in Fountain Valley, California. “There’s no formal training to deal with this — experience is your best teacher.”

Ultimately, helping a person reconceptualize what their future looks like is at the heart of every one of these conversations, said Sourav Sengupta, MD, MPH, associate professor of psychiatry and pediatrics at the Jacobs School of Medicine and Biomedical Sciences at the University at Buffalo, Buffalo, New York. “As physicians, we’re charged with helping our patients navigate a difficult and challenging time in their life,” he told this news organization.

“It’s not infrequent that patients are struggling to rethink what it will be like to be a person with an illness that might be chronic and how this will change their life,” he said.

And because denial is commonly the initial way a patient might cope with absorbing news that’s hard to hear, you’ll need to be extremely patient and empathetic.

“The goal is to build trust with this person, including trust in you, the hospital itself, and the entire team treating the patient,” Dr. Jacoub said.

“A diagnosis, especially in my field of oncology, can be scary. Spending time explaining their prognosis is very important. This can’t be a rushed scenario.”

More advice on helping patients who are in denial about their medical condition:
 

Make Sure They Understand What’s Going on

In cardiology, it’s common for patients to be hospitalized when they first learn that they have a disease they must manage for the rest of their life, said Stephanie Saucier, MD, a noninvasive cardiologist and codirector of the Women’s Heart Wellness Program at Hartford Healthcare’s Heart and Vascular Institute.

“Especially after someone has had a heart attack, a stroke, or they had bypass or stents placed, I like to see what their understanding of the disease is,” Dr. Saucier said. “I ask them, ‘What do you understand about what happened to you’. It can get confusing when you’re in the hospital and are told a lot of information in a short period of time.”
 

Share the Data

If a patient remains resistant to the news of a diagnosis, sharing test results can be beneficial. “I’ll often say, ‘here are the scans; this is the path report; this is the bloodwork; this is your biopsy report; these are the things we have’,” Dr. Jacoub said.

“Yes, this is clinical, but it helps to communicate the information you have and do it with data. For example, I might add, ‘Would you like to see some of the things [results, scans, tests] we’re talking about today?’ This also helps establish trust.”
 

Help Them Wrap Their Mind Around a Lifelong Condition

It’s often challenging for patients to accept that what they think is a one-time health issue will affect them for a lifetime. “I use juvenile diabetes as a way to explain this,” Dr. Saucier said. “I ask them what they would do if, say, their child was diagnosed with juvenile diabetes.”

Of course, patients agree that they wouldn’t give a child insulin for only a brief period. They understand that the condition must be treated in the long term. This kind of analogy can help patients understand that they, too, have a disorder requiring lifelong treatment.
 

Be Ready to Respond

Dr. Sengupta says that it’s important to be prepared with an answer if your patient is challenging or suggests that the diagnosis is fake or that you don’t have their best interests in mind.

“It’s understandable that patients might feel frustrated and upset,” he said. “It’s challenging when somehow a patient doesn’t assume my best intent.”

They might say something like, “You’re trying to make more money” or “you’re a shill for a pharma company.” In that case, you must listen. Patiently explain, “I’m your doctor; I work for you; I’m most interested in you feeling healthy and well.”

Occasionally, you’ll need a thick skin when it comes to inaccurate, controversial, or conspiratorial conversations with patients.
 

Acknowledge Differences

News of an illness may clash with a person’s take on the world. “A cancer diagnosis, for example, may clash with religious beliefs or faith-based ideology about the healthcare system,” said Aaron Fletcher, MD, a board-certified otolaryngologist specializing in head and neck surgery at the Georgia Center for Ear, Nose, Throat, and Facial Plastic Surgery in Atlanta, Georgia.

“If you have a patient who is coming to you with these beliefs, you need to have a lot of empathy, patience, and good communication skills. It’s up to you to break through the initial doubt and do your best to explain things in layman’s terms.”
 

Find Mutual Ground

If your patient still denies their health issues, try to find one thing you can agree on regarding a long-term game plan. “I’ll say, ‘Can we at least agree to discuss this with other family members or people who care about you’?” Dr. Jacoub said.

“I always tell patients that loved ones are welcome to call me so long as they [the patient] give permission. Sometimes, this is all that it takes to get them to accept their health situation.”
 

Seven Ways to Cope With Diagnosis  Denial

This news organization asked David Cutler, MD, a board-certified family medicine physician at Providence Saint John›s Health Center in Santa Monica, California, for tips in helping patients who are having a challenging time accepting their condition:

• Listen Actively. Allow the patient to express their feelings and concerns without judgment. Active listening can help them feel heard and understood, which may open the door to discussing their condition more openly.
• Provide Information. Offer factual information about their medical condition, treatment options, and the potential consequences of denial. Provide resources such as pamphlets, websites, or books that they can review at their own pace.
• Encourage Professional Help. You may want to suggest that your patient seek professional help from a therapist, counselor, or support group. A mental health professional can assist patients in processing their emotions and addressing their denial constructively.
• Involve Trusted Individuals. Enlist the support of trusted friends, family members, or healthcare professionals who can help reinforce the importance of facing their medical condition.
• Respect Autonomy. While it’s essential to encourage the person to accept their diagnosis, ultimately, the decision to get treatment lies with them. Respect their autonomy and avoid pushing them too hard, which could lead to resistance or further denial.
• Be Patient and Persistent. Overcoming denial is often a gradual process. Be patient and persistent in supporting the person, even if progress seems slow.
• Set Boundaries. It’s essential to set boundaries to protect your well-being. While you can offer support and encouragement, you cannot force someone to accept their medical condition. Recognize when your efforts are not being productive and take care of yourself in the process.

A version of this article first appeared on Medscape.com.

TOPLINE:

Patients who undergo surgery for carpal tunnel syndrome (CTS) may have an increased risk of developing incident diabetes, showed a recent study.

METHODOLOGY:

• Diabetes has been shown to be a risk factor for CTS, the most common entrapment neuropathy, but it remains unclear whether CTS is associated with subsequent diabetes.
• Researchers used data from Danish national registries to evaluate the odds of developing diabetes in 83,466 patients (median age, 54 years; 67% women) who underwent surgery for CTS between January 1996 and December 2018.
• The study compared the risk of developing diabetes in patients who had CTS surgery with that of an age- and sex-matched cohort of individuals from the general population in a 1:5 ratio (n = 417,330).
• Patients were followed (median of 7.6 years) until either a diagnosis of diabetes during hospitalization or a prescription of a glucose-lowering drug, or until either death, emigration, or the end of the study period.
• Cause-specific Cox proportional hazard models were used to compare the odds of developing diabetes between the two groups.

TAKEAWAY:

• The cumulative incidence of diabetes was higher in the CTS group than in the age-matched controls (16.8% vs 10.3%).
• Patients who underwent surgery for CTS were at a higher risk of developing diabetes within 1 year of surgery (hazard ratio [HR], 1.72) and during the rest of the study period (> 1 year: HR, 1.66).
• The risk for incident diabetes after CTS surgery was higher among younger patients aged 18-39 years (adjusted HR, 2.77) than among older patients aged 70-79 years (adjusted HR, 1.29).
• Also, patients who had bilateral surgery had a higher risk of developing diabetes than the matched control population (adjusted HR, 1.86).

IN PRACTICE:

“Identifying patients who are at risk of DM [diabetes mellitus] may mediate earlier initiation of preventive strategies. However, other factors, such as obesity and A1c levels, may affect the association,” the authors wrote.

SOURCE:

The study led by Jeppe Ravn Jacobsen, MB, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark, was published online in Diabetes, Obesity, and Metabolism .

LIMITATIONS:

The study did not find an association between CTS and a future diagnosis of type 1 diabetes, which may be attributed to the fact that patients younger than 18 years were excluded. A proportion of the patients who underwent CTS may have had undetected prediabetes or diabetes at the time of CTS surgery. Moreover, the registry lacked information on potential confounders such as body mass index, smoking history, and blood samples. The association between CTS and diabetes may be attributable to shared risk factors for both, such as obesity.

DISCLOSURES:

The study was funded by an internal grant from the Department of Cardiology, Rigshospitalet, University of Copenhagen, Denmark. The authors declared no conflicts of interest.

A version of this article first appeared on Medscape.com.

TOPLINE:

Patients who undergo surgery for carpal tunnel syndrome (CTS) may have an increased risk of developing incident diabetes, showed a recent study.

METHODOLOGY:

• Diabetes has been shown to be a risk factor for CTS, the most common entrapment neuropathy, but it remains unclear whether CTS is associated with subsequent diabetes.
• Researchers used data from Danish national registries to evaluate the odds of developing diabetes in 83,466 patients (median age, 54 years; 67% women) who underwent surgery for CTS between January 1996 and December 2018.
• The study compared the risk of developing diabetes in patients who had CTS surgery with that of an age- and sex-matched cohort of individuals from the general population in a 1:5 ratio (n = 417,330).
• Patients were followed (median of 7.6 years) until either a diagnosis of diabetes during hospitalization or a prescription of a glucose-lowering drug, or until either death, emigration, or the end of the study period.
• Cause-specific Cox proportional hazard models were used to compare the odds of developing diabetes between the two groups.

TAKEAWAY:

• The cumulative incidence of diabetes was higher in the CTS group than in the age-matched controls (16.8% vs 10.3%).
• Patients who underwent surgery for CTS were at a higher risk of developing diabetes within 1 year of surgery (hazard ratio [HR], 1.72) and during the rest of the study period (> 1 year: HR, 1.66).
• The risk for incident diabetes after CTS surgery was higher among younger patients aged 18-39 years (adjusted HR, 2.77) than among older patients aged 70-79 years (adjusted HR, 1.29).
• Also, patients who had bilateral surgery had a higher risk of developing diabetes than the matched control population (adjusted HR, 1.86).

IN PRACTICE:

“Identifying patients who are at risk of DM [diabetes mellitus] may mediate earlier initiation of preventive strategies. However, other factors, such as obesity and A1c levels, may affect the association,” the authors wrote.

SOURCE:

The study led by Jeppe Ravn Jacobsen, MB, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark, was published online in Diabetes, Obesity, and Metabolism .

LIMITATIONS:

The study did not find an association between CTS and a future diagnosis of type 1 diabetes, which may be attributed to the fact that patients younger than 18 years were excluded. A proportion of the patients who underwent CTS may have had undetected prediabetes or diabetes at the time of CTS surgery. Moreover, the registry lacked information on potential confounders such as body mass index, smoking history, and blood samples. The association between CTS and diabetes may be attributable to shared risk factors for both, such as obesity.

DISCLOSURES:

The study was funded by an internal grant from the Department of Cardiology, Rigshospitalet, University of Copenhagen, Denmark. The authors declared no conflicts of interest.

A version of this article first appeared on Medscape.com.

TOPLINE:

Patients who undergo surgery for carpal tunnel syndrome (CTS) may have an increased risk of developing incident diabetes, showed a recent study.

METHODOLOGY:

• Diabetes has been shown to be a risk factor for CTS, the most common entrapment neuropathy, but it remains unclear whether CTS is associated with subsequent diabetes.
• Researchers used data from Danish national registries to evaluate the odds of developing diabetes in 83,466 patients (median age, 54 years; 67% women) who underwent surgery for CTS between January 1996 and December 2018.
• The study compared the risk of developing diabetes in patients who had CTS surgery with that of an age- and sex-matched cohort of individuals from the general population in a 1:5 ratio (n = 417,330).
• Patients were followed (median of 7.6 years) until either a diagnosis of diabetes during hospitalization or a prescription of a glucose-lowering drug, or until either death, emigration, or the end of the study period.
• Cause-specific Cox proportional hazard models were used to compare the odds of developing diabetes between the two groups.

TAKEAWAY:

• The cumulative incidence of diabetes was higher in the CTS group than in the age-matched controls (16.8% vs 10.3%).
• Patients who underwent surgery for CTS were at a higher risk of developing diabetes within 1 year of surgery (hazard ratio [HR], 1.72) and during the rest of the study period (> 1 year: HR, 1.66).
• The risk for incident diabetes after CTS surgery was higher among younger patients aged 18-39 years (adjusted HR, 2.77) than among older patients aged 70-79 years (adjusted HR, 1.29).
• Also, patients who had bilateral surgery had a higher risk of developing diabetes than the matched control population (adjusted HR, 1.86).

IN PRACTICE:

“Identifying patients who are at risk of DM [diabetes mellitus] may mediate earlier initiation of preventive strategies. However, other factors, such as obesity and A1c levels, may affect the association,” the authors wrote.

SOURCE:

The study led by Jeppe Ravn Jacobsen, MB, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark, was published online in Diabetes, Obesity, and Metabolism .

LIMITATIONS:

The study did not find an association between CTS and a future diagnosis of type 1 diabetes, which may be attributed to the fact that patients younger than 18 years were excluded. A proportion of the patients who underwent CTS may have had undetected prediabetes or diabetes at the time of CTS surgery. Moreover, the registry lacked information on potential confounders such as body mass index, smoking history, and blood samples. The association between CTS and diabetes may be attributable to shared risk factors for both, such as obesity.

DISCLOSURES:

The study was funded by an internal grant from the Department of Cardiology, Rigshospitalet, University of Copenhagen, Denmark. The authors declared no conflicts of interest.

A version of this article first appeared on Medscape.com.

A recent study linking a niacin derivative to an increased risk for cardiovascular events has raised questions about the safety of this B vitamin, which is added to many food staples in the Western diet and taken in the form of supplements.

The findings, which were published in Nature Medicine, may also help explain why taking niacin, which lowers low-density lipoprotein cholesterol and raises high-density lipoprotein cholesterol, did not lead to a reduction in cardiovascular events in major clinical trials.

But could this essential micronutrient really have an adverse effect on cardiovascular risk, and what are the implications for niacin intake?

Senior author of the new study Stanley Hazen, MD, believes some prudence on excessive niacin intake may be justified.

“I’m not suggesting we should completely avoid niacin — it is an essential nutrient, but our results suggest that too much may be harmful,” Dr. Hazen said.

Niacin supplements are also sold with claims of antiaging effects, arthritis relief, and boosting brain function, although none of these claims have been proven. And the related compound, nicotinamide, is recommended to prevent skin cancer in high-risk patients; however, a recent study questioned that guidance.

“I would say to the general public that avoiding supplements containing niacin or related compounds could be a sensible approach at present, while these findings are investigated further.”

Other experts are unsure if such action is justified on the basis of this single study.
 

Residual Cardiovascular Risk

Dr. Hazen, who is chair of the Department of Cardiovascular & Metabolic Sciences, at the Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, explained to this news organization that they did not set out to study niacin.

“It began as a study to look for novel pathways involved in residual cardiovascular disease risk — the risk for cardiovascular events after adjusting for traditional risk factors such as cholesterol, blood pressure, and diabetes.”

The researchers began looking for compounds in plasma that predicted future adverse cardiovascular events in individuals undergoing elective diagnostic cardiac evaluation. Two of the leading candidates identified were niacin derivatives — 2PY and 4PY — that are only formed in the presence of excess niacin.

They then developed assays to measure 2PY and 4PY and conducted further studies in two validation cohorts — 2331 US individuals and a European cohort of 832 individuals. In both cohorts, elevated plasma levels of 2PY and 4PY predicted future adverse cardiovascular events, with a doubling in cardiovascular risk seen in those with levels in the highest vs the lowest quartile.

To move beyond these observational studies and to explore a potentially causal relationship, Dr. Hazen’s team went on to perform genome-wide association studies and found that genetic variants that tracked with higher levels of 4PY also linked to levels of the inflammatory marker, vascular cell adhesion molecule 1 (VCAM-1).

And in cell culture and animal studies, they found that 4PY was a driver of inflammation, upregulating VCAM-1 and eliciting vascular inflammation responses.

“So, we have shown in several different ways that the niacin derivative, 4PY, is linked to increased cardiovascular risk,” Dr. Hazen commented.
 

Significant Health Implications?

Dr. Hazen believed these findings could have significant health implications.

He noted that Western populations have been consuming large amounts of niacin ever since World War 2 when we began to fortify many foods with essential vitamins to avoid diseases caused by deficiencies. Niacin was added to foods to prevent pellagra — a disease characterized by inflamed skin, diarrhea, and dementia, that was often fatal.

“While we may have eliminated pellagra, have we, as a consequence, increased the prevalence of cardiovascular disease many years later?” Dr. Hazen asked.

This may be a clue to why niacin does not lower cardiovascular risk as much as would be expected from the degree of cholesterol lowering it brings about. “This is the niacin paradox and has led to the thought that there could be some kind of adverse effect that niacin is promoting. I think we may have found something that contributes to the niacin paradox,” he said.

However, the niacin pathway is complicated. Niacin is the major source of nicotinamide adenine dinucleotide (NAD), an integral molecule that allows cells to create energy. “Because it is so important, our bodies are designed to salvage and retain NADs, but once storage capacity is exceeded, then these 4PY and 2PY derivatives are generated,” Dr. Hazen explained. “But you have to really eat a lot of niacin-rich foods for this to happen.”

He is not claiming that niacin causes cardiovascular disease. “It is 4PY that appears to be the driver of vascular inflammation. And 4PY is a breakdown product of niacin. But there is more than one pathway that could lead to 4PY generation. There is a whole interconnecting network of compounds that interchange with each other — known as the niacin pool — any one or more of these compounds can be ingested and raise pool levels and ultimately 4PY levels. However, by far and away, niacin is one of the major sources,” Dr. Hazen commented.
 

Are High-Protein Diets Also Implicated?

Other sources of NADs include tryptophan, present in protein. And one of the genetic variants linked to changes in 4PY levels is connected to how dietary protein is directed into the niacin pool, raising the possibility that a high-protein diet may also raise cardiovascular risk in some people, Dr. Hazen noted.

Dr. Hazen estimated that about 3% of the niacin pool in a normal diet comes from protein intake, but that the percentage could increase substantially in very high–protein diets.

“Our data support the concept that if we lower our 4PY level long-term, then that would result in a reduction in cardiovascular disease. But this is still just a hypothesis. If we lower niacin intake, we will lower 4PY,” Dr. Hazen stated.

He said that this research is at too early a stage to give firm recommendations in what this means for the consumer.

“Based on these findings, I would advise people to avoid taking niacin or nicotinic acid or nicotinamide supplements and to eat a sensible balanced diet — maybe not to overdo the high protein–type diets. That’s all we can really say at the moment.”

Noting that niacin can also be one of the major components in energy drinks, he suggested it may be prudent to limit consumption of these products.
 

What Is the Optimum Niacin Intake?

Dr. Hazen noted that the recommended dietary allowance (RDA) for niacin is well known — between 14 and 18 mg, but he said the average American ingests four times that amount, and some people have substantially higher intakes — up to 50 times the RDA if taking supplements.

While food fortification with niacin may have been useful in the past, Dr. Hazen questioned whether it should still be mandated.

“In the US, you cannot buy flour or cereal or rice that is not fortified. And if you look closely, some products have much higher levels than those that are mandated. The food companies advertise this as a benefit, but there is no good data in support of that. What if several decades of eating excessive amounts of niacin has led to an increase in cardiovascular disease?”

He does not propose stopping all niacin fortification, “but maybe, we could have the choice of selecting an unfortified option,” he said.
 

Causal Link Not Proven

Commenting for this news organization, John Guyton, MD, Professor Emeritus of Medicine, Duke University Medical Center, Durham, North Carolina, who has been involved in niacin research for many years, said the Nature Medicine study showed “interesting and important results,” but they do not at this point prove a causal link between niacin intake and risk for cardiovascular disease.

“These findings need to be investigated further, and more studies are certainly justified, but I don’t think that this study alone makes an adequate case for restricting niacin intake, or thinking about stopping niacin fortification of foodstuffs,” Dr. Guyton said.

Noting that niacin is present in large quantities in many fast foods, he suggested the researchers may have just picked up the consequences of eating an unhealthy diet.

“If you look at foods that contain high quantities of niacin, red meat is at the top of the list. And if you think of a hamburger, niacin is present in relatively large quantities both the burger and the bun. So, these findings may just be a reflection of an overall unhealthy diet,” he commented.

Dr. Guyton also pointed out that major clinical trials with niacin have shown mixed results, and its effect on cardiovascular risk is still not completely understood. While the HPS2-THRIVE and AIM-HIGH trials did not show benefits in reducing cardiovascular events, an earlier study, the Coronary Drug Project in which the agent was given with food, did show some positive effects with substantial reductions in myocardial infarction and stroke, and there was the suggestion of a reduction in long-term mortality in the niacin group several years after the trial had ended.
 

Nicotinamide in Skin Cancer Prevention

What about the use of nicotinamide in skin cancer prevention?

Addressing this question, Kristin Bibee, MD, assistant professor of dermatology at Johns Hopkins University School of Medicine, Baltimore, pointed out that nicotinamide, although closely related to niacin, may have different effects. “This study does not specifically address nicotinamide supplementation and 4PY levels,” she said.

Diona Damian, MD, professor of dermatology at the University of Sydney, Camperdown, Australia, told this news organization that it was hard to extrapolate these findings on basal levels of niacin in a cardiac cohort to the administration of supra-physiological doses of nicotinamide for skin cancer prevention.

There may be different effects of supplemental niacin compared to nicotinamide, which lacks the vasodilatory effects seen with niacin, Dr. Damian said, adding that it would be interesting to see the results from higher, therapeutic nicotinamide doses in patients with and without cardiac disease.

She pointed out that high vs low levels of nicotinamide supplementation can have different and even opposite effects on cellular processes, such as upregulating or inhibiting DNA repair enzymes. At high doses, nicotinamide is anti-inflammatory in skin.

Dr. Damian noted that two phase 3 studies (ONTRAC and ONTRANS) of nicotinamide 500 mg twice daily for skin cancer prevention did not find a significant increase in cardiovascular events compared to placebo over 12 months.

“Oral nicotinamide has been shown to reduce nonmelanoma skin cancer by about a quarter in patients with normal immunity and multiple skin cancers. The doses used for skin cancer prevention are well above daily dietary levels, and treatment needs to be ongoing for the protective effects to continue. Nicotinamide should not be recommended as a preventive agent for people who have not had multiple skin cancers but should be reserved for those with a heavy burden of skin cancers,” she commented.

“For now, it would be reasonable to balance the benefits of skin cancer reduction against possible effects on inflammatory markers in patients with cardiac risk factors, when helping patients to decide whether or not nicotinamide therapy is appropriate for them,” she added.

Meanwhile, Dr. Hazen said the most exciting part of this new research is the discovery of a new pathway that contributes to cardiovascular disease and potentially a new target to treat residual cardiovascular risk.

“I believe our results show that we should be measuring 4PY levels and individuals with high levels need to be extra vigilant about lowering their cardiovascular risk.”

The next step will be to confirm these results in other populations and then to develop a diagnostic test to identify people with a high 4PY level, he said.

A version of this article appeared on Medscape.com.

A recent study linking a niacin derivative to an increased risk for cardiovascular events has raised questions about the safety of this B vitamin, which is added to many food staples in the Western diet and taken in the form of supplements.

The findings, which were published in Nature Medicine, may also help explain why taking niacin, which lowers low-density lipoprotein cholesterol and raises high-density lipoprotein cholesterol, did not lead to a reduction in cardiovascular events in major clinical trials.

But could this essential micronutrient really have an adverse effect on cardiovascular risk, and what are the implications for niacin intake?

Senior author of the new study Stanley Hazen, MD, believes some prudence on excessive niacin intake may be justified.

“I’m not suggesting we should completely avoid niacin — it is an essential nutrient, but our results suggest that too much may be harmful,” Dr. Hazen said.

Niacin supplements are also sold with claims of antiaging effects, arthritis relief, and boosting brain function, although none of these claims have been proven. And the related compound, nicotinamide, is recommended to prevent skin cancer in high-risk patients; however, a recent study questioned that guidance.

“I would say to the general public that avoiding supplements containing niacin or related compounds could be a sensible approach at present, while these findings are investigated further.”

Other experts are unsure if such action is justified on the basis of this single study.
 

Residual Cardiovascular Risk

Dr. Hazen, who is chair of the Department of Cardiovascular & Metabolic Sciences, at the Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, explained to this news organization that they did not set out to study niacin.

“It began as a study to look for novel pathways involved in residual cardiovascular disease risk — the risk for cardiovascular events after adjusting for traditional risk factors such as cholesterol, blood pressure, and diabetes.”

The researchers began looking for compounds in plasma that predicted future adverse cardiovascular events in individuals undergoing elective diagnostic cardiac evaluation. Two of the leading candidates identified were niacin derivatives — 2PY and 4PY — that are only formed in the presence of excess niacin.

They then developed assays to measure 2PY and 4PY and conducted further studies in two validation cohorts — 2331 US individuals and a European cohort of 832 individuals. In both cohorts, elevated plasma levels of 2PY and 4PY predicted future adverse cardiovascular events, with a doubling in cardiovascular risk seen in those with levels in the highest vs the lowest quartile.

To move beyond these observational studies and to explore a potentially causal relationship, Dr. Hazen’s team went on to perform genome-wide association studies and found that genetic variants that tracked with higher levels of 4PY also linked to levels of the inflammatory marker, vascular cell adhesion molecule 1 (VCAM-1).

And in cell culture and animal studies, they found that 4PY was a driver of inflammation, upregulating VCAM-1 and eliciting vascular inflammation responses.

“So, we have shown in several different ways that the niacin derivative, 4PY, is linked to increased cardiovascular risk,” Dr. Hazen commented.
 

Significant Health Implications?

Dr. Hazen believed these findings could have significant health implications.

He noted that Western populations have been consuming large amounts of niacin ever since World War 2 when we began to fortify many foods with essential vitamins to avoid diseases caused by deficiencies. Niacin was added to foods to prevent pellagra — a disease characterized by inflamed skin, diarrhea, and dementia, that was often fatal.

“While we may have eliminated pellagra, have we, as a consequence, increased the prevalence of cardiovascular disease many years later?” Dr. Hazen asked.

This may be a clue to why niacin does not lower cardiovascular risk as much as would be expected from the degree of cholesterol lowering it brings about. “This is the niacin paradox and has led to the thought that there could be some kind of adverse effect that niacin is promoting. I think we may have found something that contributes to the niacin paradox,” he said.

However, the niacin pathway is complicated. Niacin is the major source of nicotinamide adenine dinucleotide (NAD), an integral molecule that allows cells to create energy. “Because it is so important, our bodies are designed to salvage and retain NADs, but once storage capacity is exceeded, then these 4PY and 2PY derivatives are generated,” Dr. Hazen explained. “But you have to really eat a lot of niacin-rich foods for this to happen.”

He is not claiming that niacin causes cardiovascular disease. “It is 4PY that appears to be the driver of vascular inflammation. And 4PY is a breakdown product of niacin. But there is more than one pathway that could lead to 4PY generation. There is a whole interconnecting network of compounds that interchange with each other — known as the niacin pool — any one or more of these compounds can be ingested and raise pool levels and ultimately 4PY levels. However, by far and away, niacin is one of the major sources,” Dr. Hazen commented.
 

Are High-Protein Diets Also Implicated?

Other sources of NADs include tryptophan, present in protein. And one of the genetic variants linked to changes in 4PY levels is connected to how dietary protein is directed into the niacin pool, raising the possibility that a high-protein diet may also raise cardiovascular risk in some people, Dr. Hazen noted.

Dr. Hazen estimated that about 3% of the niacin pool in a normal diet comes from protein intake, but that the percentage could increase substantially in very high–protein diets.

“Our data support the concept that if we lower our 4PY level long-term, then that would result in a reduction in cardiovascular disease. But this is still just a hypothesis. If we lower niacin intake, we will lower 4PY,” Dr. Hazen stated.

He said that this research is at too early a stage to give firm recommendations in what this means for the consumer.

“Based on these findings, I would advise people to avoid taking niacin or nicotinic acid or nicotinamide supplements and to eat a sensible balanced diet — maybe not to overdo the high protein–type diets. That’s all we can really say at the moment.”

Noting that niacin can also be one of the major components in energy drinks, he suggested it may be prudent to limit consumption of these products.
 

What Is the Optimum Niacin Intake?

Dr. Hazen noted that the recommended dietary allowance (RDA) for niacin is well known — between 14 and 18 mg, but he said the average American ingests four times that amount, and some people have substantially higher intakes — up to 50 times the RDA if taking supplements.

While food fortification with niacin may have been useful in the past, Dr. Hazen questioned whether it should still be mandated.

“In the US, you cannot buy flour or cereal or rice that is not fortified. And if you look closely, some products have much higher levels than those that are mandated. The food companies advertise this as a benefit, but there is no good data in support of that. What if several decades of eating excessive amounts of niacin has led to an increase in cardiovascular disease?”

He does not propose stopping all niacin fortification, “but maybe, we could have the choice of selecting an unfortified option,” he said.
 

Causal Link Not Proven

Commenting for this news organization, John Guyton, MD, Professor Emeritus of Medicine, Duke University Medical Center, Durham, North Carolina, who has been involved in niacin research for many years, said the Nature Medicine study showed “interesting and important results,” but they do not at this point prove a causal link between niacin intake and risk for cardiovascular disease.

“These findings need to be investigated further, and more studies are certainly justified, but I don’t think that this study alone makes an adequate case for restricting niacin intake, or thinking about stopping niacin fortification of foodstuffs,” Dr. Guyton said.

Noting that niacin is present in large quantities in many fast foods, he suggested the researchers may have just picked up the consequences of eating an unhealthy diet.

“If you look at foods that contain high quantities of niacin, red meat is at the top of the list. And if you think of a hamburger, niacin is present in relatively large quantities both the burger and the bun. So, these findings may just be a reflection of an overall unhealthy diet,” he commented.

Dr. Guyton also pointed out that major clinical trials with niacin have shown mixed results, and its effect on cardiovascular risk is still not completely understood. While the HPS2-THRIVE and AIM-HIGH trials did not show benefits in reducing cardiovascular events, an earlier study, the Coronary Drug Project in which the agent was given with food, did show some positive effects with substantial reductions in myocardial infarction and stroke, and there was the suggestion of a reduction in long-term mortality in the niacin group several years after the trial had ended.
 

Nicotinamide in Skin Cancer Prevention

What about the use of nicotinamide in skin cancer prevention?

Addressing this question, Kristin Bibee, MD, assistant professor of dermatology at Johns Hopkins University School of Medicine, Baltimore, pointed out that nicotinamide, although closely related to niacin, may have different effects. “This study does not specifically address nicotinamide supplementation and 4PY levels,” she said.

Diona Damian, MD, professor of dermatology at the University of Sydney, Camperdown, Australia, told this news organization that it was hard to extrapolate these findings on basal levels of niacin in a cardiac cohort to the administration of supra-physiological doses of nicotinamide for skin cancer prevention.

There may be different effects of supplemental niacin compared to nicotinamide, which lacks the vasodilatory effects seen with niacin, Dr. Damian said, adding that it would be interesting to see the results from higher, therapeutic nicotinamide doses in patients with and without cardiac disease.

She pointed out that high vs low levels of nicotinamide supplementation can have different and even opposite effects on cellular processes, such as upregulating or inhibiting DNA repair enzymes. At high doses, nicotinamide is anti-inflammatory in skin.

Dr. Damian noted that two phase 3 studies (ONTRAC and ONTRANS) of nicotinamide 500 mg twice daily for skin cancer prevention did not find a significant increase in cardiovascular events compared to placebo over 12 months.

“Oral nicotinamide has been shown to reduce nonmelanoma skin cancer by about a quarter in patients with normal immunity and multiple skin cancers. The doses used for skin cancer prevention are well above daily dietary levels, and treatment needs to be ongoing for the protective effects to continue. Nicotinamide should not be recommended as a preventive agent for people who have not had multiple skin cancers but should be reserved for those with a heavy burden of skin cancers,” she commented.

“For now, it would be reasonable to balance the benefits of skin cancer reduction against possible effects on inflammatory markers in patients with cardiac risk factors, when helping patients to decide whether or not nicotinamide therapy is appropriate for them,” she added.

Meanwhile, Dr. Hazen said the most exciting part of this new research is the discovery of a new pathway that contributes to cardiovascular disease and potentially a new target to treat residual cardiovascular risk.

“I believe our results show that we should be measuring 4PY levels and individuals with high levels need to be extra vigilant about lowering their cardiovascular risk.”

The next step will be to confirm these results in other populations and then to develop a diagnostic test to identify people with a high 4PY level, he said.

A version of this article appeared on Medscape.com.

A recent study linking a niacin derivative to an increased risk for cardiovascular events has raised questions about the safety of this B vitamin, which is added to many food staples in the Western diet and taken in the form of supplements.

The findings, which were published in Nature Medicine, may also help explain why taking niacin, which lowers low-density lipoprotein cholesterol and raises high-density lipoprotein cholesterol, did not lead to a reduction in cardiovascular events in major clinical trials.

But could this essential micronutrient really have an adverse effect on cardiovascular risk, and what are the implications for niacin intake?

Senior author of the new study Stanley Hazen, MD, believes some prudence on excessive niacin intake may be justified.

“I’m not suggesting we should completely avoid niacin — it is an essential nutrient, but our results suggest that too much may be harmful,” Dr. Hazen said.

Niacin supplements are also sold with claims of antiaging effects, arthritis relief, and boosting brain function, although none of these claims have been proven. And the related compound, nicotinamide, is recommended to prevent skin cancer in high-risk patients; however, a recent study questioned that guidance.

“I would say to the general public that avoiding supplements containing niacin or related compounds could be a sensible approach at present, while these findings are investigated further.”

Other experts are unsure if such action is justified on the basis of this single study.
 

Residual Cardiovascular Risk

Dr. Hazen, who is chair of the Department of Cardiovascular & Metabolic Sciences, at the Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, explained to this news organization that they did not set out to study niacin.

“It began as a study to look for novel pathways involved in residual cardiovascular disease risk — the risk for cardiovascular events after adjusting for traditional risk factors such as cholesterol, blood pressure, and diabetes.”

The researchers began looking for compounds in plasma that predicted future adverse cardiovascular events in individuals undergoing elective diagnostic cardiac evaluation. Two of the leading candidates identified were niacin derivatives — 2PY and 4PY — that are only formed in the presence of excess niacin.

They then developed assays to measure 2PY and 4PY and conducted further studies in two validation cohorts — 2331 US individuals and a European cohort of 832 individuals. In both cohorts, elevated plasma levels of 2PY and 4PY predicted future adverse cardiovascular events, with a doubling in cardiovascular risk seen in those with levels in the highest vs the lowest quartile.

To move beyond these observational studies and to explore a potentially causal relationship, Dr. Hazen’s team went on to perform genome-wide association studies and found that genetic variants that tracked with higher levels of 4PY also linked to levels of the inflammatory marker, vascular cell adhesion molecule 1 (VCAM-1).

And in cell culture and animal studies, they found that 4PY was a driver of inflammation, upregulating VCAM-1 and eliciting vascular inflammation responses.

“So, we have shown in several different ways that the niacin derivative, 4PY, is linked to increased cardiovascular risk,” Dr. Hazen commented.
 

Significant Health Implications?

Dr. Hazen believed these findings could have significant health implications.

He noted that Western populations have been consuming large amounts of niacin ever since World War 2 when we began to fortify many foods with essential vitamins to avoid diseases caused by deficiencies. Niacin was added to foods to prevent pellagra — a disease characterized by inflamed skin, diarrhea, and dementia, that was often fatal.

“While we may have eliminated pellagra, have we, as a consequence, increased the prevalence of cardiovascular disease many years later?” Dr. Hazen asked.

This may be a clue to why niacin does not lower cardiovascular risk as much as would be expected from the degree of cholesterol lowering it brings about. “This is the niacin paradox and has led to the thought that there could be some kind of adverse effect that niacin is promoting. I think we may have found something that contributes to the niacin paradox,” he said.

However, the niacin pathway is complicated. Niacin is the major source of nicotinamide adenine dinucleotide (NAD), an integral molecule that allows cells to create energy. “Because it is so important, our bodies are designed to salvage and retain NADs, but once storage capacity is exceeded, then these 4PY and 2PY derivatives are generated,” Dr. Hazen explained. “But you have to really eat a lot of niacin-rich foods for this to happen.”

He is not claiming that niacin causes cardiovascular disease. “It is 4PY that appears to be the driver of vascular inflammation. And 4PY is a breakdown product of niacin. But there is more than one pathway that could lead to 4PY generation. There is a whole interconnecting network of compounds that interchange with each other — known as the niacin pool — any one or more of these compounds can be ingested and raise pool levels and ultimately 4PY levels. However, by far and away, niacin is one of the major sources,” Dr. Hazen commented.
 

Are High-Protein Diets Also Implicated?

Other sources of NADs include tryptophan, present in protein. And one of the genetic variants linked to changes in 4PY levels is connected to how dietary protein is directed into the niacin pool, raising the possibility that a high-protein diet may also raise cardiovascular risk in some people, Dr. Hazen noted.

Dr. Hazen estimated that about 3% of the niacin pool in a normal diet comes from protein intake, but that the percentage could increase substantially in very high–protein diets.

“Our data support the concept that if we lower our 4PY level long-term, then that would result in a reduction in cardiovascular disease. But this is still just a hypothesis. If we lower niacin intake, we will lower 4PY,” Dr. Hazen stated.

He said that this research is at too early a stage to give firm recommendations in what this means for the consumer.

“Based on these findings, I would advise people to avoid taking niacin or nicotinic acid or nicotinamide supplements and to eat a sensible balanced diet — maybe not to overdo the high protein–type diets. That’s all we can really say at the moment.”

Noting that niacin can also be one of the major components in energy drinks, he suggested it may be prudent to limit consumption of these products.
 

What Is the Optimum Niacin Intake?

Dr. Hazen noted that the recommended dietary allowance (RDA) for niacin is well known — between 14 and 18 mg, but he said the average American ingests four times that amount, and some people have substantially higher intakes — up to 50 times the RDA if taking supplements.

While food fortification with niacin may have been useful in the past, Dr. Hazen questioned whether it should still be mandated.

“In the US, you cannot buy flour or cereal or rice that is not fortified. And if you look closely, some products have much higher levels than those that are mandated. The food companies advertise this as a benefit, but there is no good data in support of that. What if several decades of eating excessive amounts of niacin has led to an increase in cardiovascular disease?”

He does not propose stopping all niacin fortification, “but maybe, we could have the choice of selecting an unfortified option,” he said.
 

Causal Link Not Proven

Commenting for this news organization, John Guyton, MD, Professor Emeritus of Medicine, Duke University Medical Center, Durham, North Carolina, who has been involved in niacin research for many years, said the Nature Medicine study showed “interesting and important results,” but they do not at this point prove a causal link between niacin intake and risk for cardiovascular disease.

“These findings need to be investigated further, and more studies are certainly justified, but I don’t think that this study alone makes an adequate case for restricting niacin intake, or thinking about stopping niacin fortification of foodstuffs,” Dr. Guyton said.

Noting that niacin is present in large quantities in many fast foods, he suggested the researchers may have just picked up the consequences of eating an unhealthy diet.

“If you look at foods that contain high quantities of niacin, red meat is at the top of the list. And if you think of a hamburger, niacin is present in relatively large quantities both the burger and the bun. So, these findings may just be a reflection of an overall unhealthy diet,” he commented.

Dr. Guyton also pointed out that major clinical trials with niacin have shown mixed results, and its effect on cardiovascular risk is still not completely understood. While the HPS2-THRIVE and AIM-HIGH trials did not show benefits in reducing cardiovascular events, an earlier study, the Coronary Drug Project in which the agent was given with food, did show some positive effects with substantial reductions in myocardial infarction and stroke, and there was the suggestion of a reduction in long-term mortality in the niacin group several years after the trial had ended.
 

Nicotinamide in Skin Cancer Prevention

What about the use of nicotinamide in skin cancer prevention?

Addressing this question, Kristin Bibee, MD, assistant professor of dermatology at Johns Hopkins University School of Medicine, Baltimore, pointed out that nicotinamide, although closely related to niacin, may have different effects. “This study does not specifically address nicotinamide supplementation and 4PY levels,” she said.

Diona Damian, MD, professor of dermatology at the University of Sydney, Camperdown, Australia, told this news organization that it was hard to extrapolate these findings on basal levels of niacin in a cardiac cohort to the administration of supra-physiological doses of nicotinamide for skin cancer prevention.

There may be different effects of supplemental niacin compared to nicotinamide, which lacks the vasodilatory effects seen with niacin, Dr. Damian said, adding that it would be interesting to see the results from higher, therapeutic nicotinamide doses in patients with and without cardiac disease.

She pointed out that high vs low levels of nicotinamide supplementation can have different and even opposite effects on cellular processes, such as upregulating or inhibiting DNA repair enzymes. At high doses, nicotinamide is anti-inflammatory in skin.

Dr. Damian noted that two phase 3 studies (ONTRAC and ONTRANS) of nicotinamide 500 mg twice daily for skin cancer prevention did not find a significant increase in cardiovascular events compared to placebo over 12 months.

“Oral nicotinamide has been shown to reduce nonmelanoma skin cancer by about a quarter in patients with normal immunity and multiple skin cancers. The doses used for skin cancer prevention are well above daily dietary levels, and treatment needs to be ongoing for the protective effects to continue. Nicotinamide should not be recommended as a preventive agent for people who have not had multiple skin cancers but should be reserved for those with a heavy burden of skin cancers,” she commented.

“For now, it would be reasonable to balance the benefits of skin cancer reduction against possible effects on inflammatory markers in patients with cardiac risk factors, when helping patients to decide whether or not nicotinamide therapy is appropriate for them,” she added.

Meanwhile, Dr. Hazen said the most exciting part of this new research is the discovery of a new pathway that contributes to cardiovascular disease and potentially a new target to treat residual cardiovascular risk.

“I believe our results show that we should be measuring 4PY levels and individuals with high levels need to be extra vigilant about lowering their cardiovascular risk.”

The next step will be to confirm these results in other populations and then to develop a diagnostic test to identify people with a high 4PY level, he said.

A version of this article appeared on Medscape.com.

Presentation

A 63-year-old man presented to his primary care provider with ptosis, diplopia, dysphagia, and fatigue/weakness of arms and shoulders after mild activity (eg, raking leaves in his yard, carrying groceries, housework). His ocular symptoms had been present for about 5 months but his arm/shoulder muscle weakness was recent.

Physical examination revealed weakness after repeated/sustained muscle contraction followed by improvement with rest or an ice-pack test (see "Diagnosis" below), and a tentative diagnosis of generalized myasthenia gravis (gMG) was made. The patient was referred to a neurologist for serologic testing, which was positive for anti-AChR MG antibody, confirming the diagnosis of gMG.

Treatment was initiated with pyridostigmine, with reevaluation and treatment escalation as necessary.

gMG is generally defined as a process beginning with localized manifestations of MG, typically ocular muscle involvement. In some patients it remains localized and is considered ocular MG, while in the remaining patients it becomes generalized, most often within 1 year of onset. 

Clinical findings in patients presenting with gMG can include:

• Extraocular muscle weakness (85% of patients) causing diplopia, ptosis, or both

• Bulbar muscle weakness (15% of patients)

  • Difficulty chewing, dysphagia, hoarseness, dysarthria 

  • Facial muscle involvement causing inability to show facial expressions, and neck muscle involvement impairing head posture (dropped-head syndrome)

• Limb weakness

  • Upper limbs more affected than lower

  • Proximal muscles involved more than distal

• Myasthenic crisis, considered a medical emergency due to weakness of the diaphragm and intercostal muscles, secondary to a lower respiratory tract infection

Differential Diagnosis

Several potential diagnoses should be considered on the basis of this patient's presentation.

• Lambert-Eaton myasthenic syndrome: An autoimmune or paraneoplastic disorder producing fluctuating muscle weakness that improves with physical activity, differentiating it from MG

• Cavernous sinus thrombosis: Also called cavernous sinus syndrome, can present with persistent ocular findings, photophobia, chemosis, and headache

• Brainstem gliomas: Can present with dysphagia, muscle weakness, diplopia, drooping eyelids, slurred speech, and/or difficulty breathing

• Multiple sclerosis: Can present with a range of typically fluctuating clinical features, including but not limited to the classic findings of paresthesias, spinal cord and cerebellar symptoms, optic neuritis, diplopia, trigeminal neuralgia, and fatigue

• Botulism: Can present with ptosis, diplopia, difficulty moving the eyes, progressive weakness, and difficulty breathing caused by a toxin produced by Clostridium botulinum

• Tickborne disease: Can present with headache, fatigue, myalgia, rash, and arthralgia, which can mimic the symptoms of other diseases

• Polymyositis/dermatomyositis: Characteristically present with symmetrical proximal muscle weakness, typical rash (dermatomyositis only), elevated serum muscle enzymes, anti-muscle antibodies, and myopathic changes on electromyography

• Graves ophthalmopathy: Also known as thyroid eye disease, can present with photophobia, eye discomfort including gritty eye sensations, lacrimation or dry eye, proptosis, diplopia, and eyelid retraction

• Thyrotoxicosis: Can present with heat intolerance, palpitations, anxiety, fatigue, weight loss, and muscle weakness

Diagnosis

On the basis of this patient's clinical presentation and serology, his diagnosis is generalized AChR MG, class III.

Table. Myasthenia Gravis Foundation of America Clinical Classification 

Commonly performed tests and diagnostic criteria in patients with suspected MG include:

• History/physical examination

• Serology

  • AChR antibody is highly specific (80% positive in gMG, approximately 50% positive in ocular MG)

  • Anti-MUSK antibody (approximately 20% positive, typically in patients negative for AChR antibody)

  • Anti-LRP4 antibody, in patients negative for anti-AChR or anti-MUSK antibody

Detecting established pathogenic antibodies against some synaptic molecules in a patient with clinical features of MG is virtually diagnostic. The presence of AChR antibody confirmed the diagnosis in the case presented above. Although the titer of AChR autoantibodies does not correlate with disease severity, fluctuations in titers in an individual patient have been reported to correlate with the severity of muscle weakness and to predict exacerbations. Accordingly, serial testing for AChR autoantibodies can influence therapeutic decisions.

• Electrodiagnostic studies (useful in patients with negative serology)

  • Repetitive nerve stimulation 

  • Single-fiber electromyography 

• Tests to help confirm that ocular symptoms are due to MG in the absence of positive serology

  • Edrophonium (Tensilon) test: Can induce dramatic but only short-term recovery from symptoms (particularly ocular symptoms)

  • Ice-pack test: Used mainly in ocular MG, in which it can temporarily improve ptosis

• Chest CT/MRI, to screen for thymoma in patients with MG

• Laboratory tests to screen for other autoimmune diseases, including rheumatoid arthritis (rheumatoid factor), systemic lupus erythematosus (ANA), and thyroid eye disease (anti-thyroid antibodies), which may occur concomitantly with MG

Management

The most recent recommendations for management of MG were published in 2021, updating the 2016 International Consensus Guidance for Management of Myasthenia Gravis by the Myasthenia Gravis Foundation of America.

MG can be managed pharmacologically and nonpharmacologically. Pharmacologic treatment includes acetylcholinesterase inhibitors, biologics, and immunosuppressive/immunomodulatory agents. Corticosteroids are used primarily in patients with clinically significant, severe muscle weakness and/or poor response to acetylcholinesterase inhibitors (pyridostigmine).

• Pharmacotherapy

  • Acetylcholinesterase inhibitors

    • Pyridostigmine, an acetylcholinesterase inhibitor used for symptomatic treatment and maintenance therapy, is the only agent in this class used routinely in the clinical setting of MG

  • Biologics

    • Rituximab, a chimeric CD20-directed cytolytic antibody that mediates lysis of B lymphocytes

    • Eculizumab, a humanized monoclonal antibody that specifically binds to the complement protein C5 with high affinity, preventing formation of membrane attack protein (MAC) 

    • Rozanolixizumab, a neonatal Fc receptor blocker that decreases circulating IgG

    • Ravulizumab, a terminal complement inhibitor that specifically binds to complement C5, preventing MAC formation

    • Efgartigimod alfa injection, a neonatal Fc receptor blocker that decreases circulating IgG, with or without hyaluronidase, which increases permeability of subcutaneous tissue by depolymerizing hyaluronan

    • Zilucoplan, a complement protein C5 inhibitor that inhibits its cleavage to C5a and C5b, preventing the generation of the terminal complement complex, C5b-9

  • Immunosuppressive/immunomodulatory agents

    • Tacrolimus, a calcineurin inhibitor

    • Methotrexate, a dihydrofolate reductase inhibitor

    • Cyclosporine, a P-glycoprotein inhibitor and calcineurin inhibitor that also inhibits cytochrome P450 3A4

• Nonpharmacologic therapy

  • Thymectomy, to eliminate a major source of B and T lymphocytes and plasma cells, which produce anti-AChR antibody

  • PLEX (plasmapheresis; plasma exchange), to remove autoantibodies from the circulation

  • IVIg (intravenous immune globulin), recommended perioperatively to stabilize a patient and for management of myasthenic crises because of its rapid onset of action

Prognosis

In patients with gMG, the time to maximal weakness usually is within the first 3 years of disease onset. Accordingly, half of the disease-related mortality also occurs during this period, after which a steady state or improvement occurs. Younger age at onset (< 40 years), early thymectomy, and treatment with corticosteroids have been found to be associated with reduced risk for relapse, and thymectomy results in complete remission of the disease in some patients.

Most affected individuals have a normal lifespan. Morbidity includes quality-of-life issues resulting from muscle weakness, side effects from treatment (long-term effects of corticosteroids used for immunosuppression), and myasthenic crisis (mortality rate, 4.47%). Prognostic factors to be assessed at diagnosis may include:

• Risk for secondary generalization: associated with late age of onset, high AChR antibody titers, thymoma, and presence of both ptosis and diplopia

• Risk for MG relapse: reduced risk for relapse at age < 40 years at onset, early thymectomy, and prednisolone use. Increased risk for relapse with anti-Kv1.4 antibodies and concomitant autoimmune disease.

• Morbidity results from fluctuating impairment of muscle strength, which may result in falls, aspiration, pneumonia, and ventilatory failure.

• Principle risk factors for mortality include age of onset > 40 years, rapid progression of symptoms, and thymoma.

Clinical Takeaway

gMG is an autoimmune disease caused by an antibody-mediated postsynaptic blockade of neuromuscular transmission affecting the acetylcholine receptor. It presents as fatigable muscle weakness, which must be differentiated from other conditions with similar clinical presentations. Decreased muscle strength in patients with gMG can affect quality of life. In severe cases, untreated gMG can lead to myasthenic crisis, a potentially fatal complication due to pneumonia resulting from respiratory muscle weakness. 

Many of the newest therapies, both approved and pending, are targeting specific autoimmune components of the immune system, which are mostly well defined in gMG.

Presentation

A 63-year-old man presented to his primary care provider with ptosis, diplopia, dysphagia, and fatigue/weakness of arms and shoulders after mild activity (eg, raking leaves in his yard, carrying groceries, housework). His ocular symptoms had been present for about 5 months but his arm/shoulder muscle weakness was recent.

Physical examination revealed weakness after repeated/sustained muscle contraction followed by improvement with rest or an ice-pack test (see "Diagnosis" below), and a tentative diagnosis of generalized myasthenia gravis (gMG) was made. The patient was referred to a neurologist for serologic testing, which was positive for anti-AChR MG antibody, confirming the diagnosis of gMG.

Treatment was initiated with pyridostigmine, with reevaluation and treatment escalation as necessary.

gMG is generally defined as a process beginning with localized manifestations of MG, typically ocular muscle involvement. In some patients it remains localized and is considered ocular MG, while in the remaining patients it becomes generalized, most often within 1 year of onset. 

Clinical findings in patients presenting with gMG can include:

• Extraocular muscle weakness (85% of patients) causing diplopia, ptosis, or both

• Bulbar muscle weakness (15% of patients)

  • Difficulty chewing, dysphagia, hoarseness, dysarthria 

  • Facial muscle involvement causing inability to show facial expressions, and neck muscle involvement impairing head posture (dropped-head syndrome)

• Limb weakness

  • Upper limbs more affected than lower

  • Proximal muscles involved more than distal

• Myasthenic crisis, considered a medical emergency due to weakness of the diaphragm and intercostal muscles, secondary to a lower respiratory tract infection

Differential Diagnosis

Several potential diagnoses should be considered on the basis of this patient's presentation.

• Lambert-Eaton myasthenic syndrome: An autoimmune or paraneoplastic disorder producing fluctuating muscle weakness that improves with physical activity, differentiating it from MG

• Cavernous sinus thrombosis: Also called cavernous sinus syndrome, can present with persistent ocular findings, photophobia, chemosis, and headache

• Brainstem gliomas: Can present with dysphagia, muscle weakness, diplopia, drooping eyelids, slurred speech, and/or difficulty breathing

• Multiple sclerosis: Can present with a range of typically fluctuating clinical features, including but not limited to the classic findings of paresthesias, spinal cord and cerebellar symptoms, optic neuritis, diplopia, trigeminal neuralgia, and fatigue

• Botulism: Can present with ptosis, diplopia, difficulty moving the eyes, progressive weakness, and difficulty breathing caused by a toxin produced by Clostridium botulinum

• Tickborne disease: Can present with headache, fatigue, myalgia, rash, and arthralgia, which can mimic the symptoms of other diseases

• Polymyositis/dermatomyositis: Characteristically present with symmetrical proximal muscle weakness, typical rash (dermatomyositis only), elevated serum muscle enzymes, anti-muscle antibodies, and myopathic changes on electromyography

• Graves ophthalmopathy: Also known as thyroid eye disease, can present with photophobia, eye discomfort including gritty eye sensations, lacrimation or dry eye, proptosis, diplopia, and eyelid retraction

• Thyrotoxicosis: Can present with heat intolerance, palpitations, anxiety, fatigue, weight loss, and muscle weakness

Diagnosis

On the basis of this patient's clinical presentation and serology, his diagnosis is generalized AChR MG, class III.

Table. Myasthenia Gravis Foundation of America Clinical Classification 

Commonly performed tests and diagnostic criteria in patients with suspected MG include:

• History/physical examination

• Serology

  • AChR antibody is highly specific (80% positive in gMG, approximately 50% positive in ocular MG)

  • Anti-MUSK antibody (approximately 20% positive, typically in patients negative for AChR antibody)

  • Anti-LRP4 antibody, in patients negative for anti-AChR or anti-MUSK antibody

Detecting established pathogenic antibodies against some synaptic molecules in a patient with clinical features of MG is virtually diagnostic. The presence of AChR antibody confirmed the diagnosis in the case presented above. Although the titer of AChR autoantibodies does not correlate with disease severity, fluctuations in titers in an individual patient have been reported to correlate with the severity of muscle weakness and to predict exacerbations. Accordingly, serial testing for AChR autoantibodies can influence therapeutic decisions.

• Electrodiagnostic studies (useful in patients with negative serology)

  • Repetitive nerve stimulation 

  • Single-fiber electromyography 

• Tests to help confirm that ocular symptoms are due to MG in the absence of positive serology

  • Edrophonium (Tensilon) test: Can induce dramatic but only short-term recovery from symptoms (particularly ocular symptoms)

  • Ice-pack test: Used mainly in ocular MG, in which it can temporarily improve ptosis

• Chest CT/MRI, to screen for thymoma in patients with MG

• Laboratory tests to screen for other autoimmune diseases, including rheumatoid arthritis (rheumatoid factor), systemic lupus erythematosus (ANA), and thyroid eye disease (anti-thyroid antibodies), which may occur concomitantly with MG

Management

The most recent recommendations for management of MG were published in 2021, updating the 2016 International Consensus Guidance for Management of Myasthenia Gravis by the Myasthenia Gravis Foundation of America.

MG can be managed pharmacologically and nonpharmacologically. Pharmacologic treatment includes acetylcholinesterase inhibitors, biologics, and immunosuppressive/immunomodulatory agents. Corticosteroids are used primarily in patients with clinically significant, severe muscle weakness and/or poor response to acetylcholinesterase inhibitors (pyridostigmine).

• Pharmacotherapy

  • Acetylcholinesterase inhibitors

    • Pyridostigmine, an acetylcholinesterase inhibitor used for symptomatic treatment and maintenance therapy, is the only agent in this class used routinely in the clinical setting of MG

  • Biologics

    • Rituximab, a chimeric CD20-directed cytolytic antibody that mediates lysis of B lymphocytes

    • Eculizumab, a humanized monoclonal antibody that specifically binds to the complement protein C5 with high affinity, preventing formation of membrane attack protein (MAC) 

    • Rozanolixizumab, a neonatal Fc receptor blocker that decreases circulating IgG

    • Ravulizumab, a terminal complement inhibitor that specifically binds to complement C5, preventing MAC formation

    • Efgartigimod alfa injection, a neonatal Fc receptor blocker that decreases circulating IgG, with or without hyaluronidase, which increases permeability of subcutaneous tissue by depolymerizing hyaluronan

    • Zilucoplan, a complement protein C5 inhibitor that inhibits its cleavage to C5a and C5b, preventing the generation of the terminal complement complex, C5b-9

  • Immunosuppressive/immunomodulatory agents

    • Tacrolimus, a calcineurin inhibitor

    • Methotrexate, a dihydrofolate reductase inhibitor

    • Cyclosporine, a P-glycoprotein inhibitor and calcineurin inhibitor that also inhibits cytochrome P450 3A4

• Nonpharmacologic therapy

  • Thymectomy, to eliminate a major source of B and T lymphocytes and plasma cells, which produce anti-AChR antibody

  • PLEX (plasmapheresis; plasma exchange), to remove autoantibodies from the circulation

  • IVIg (intravenous immune globulin), recommended perioperatively to stabilize a patient and for management of myasthenic crises because of its rapid onset of action

Prognosis

In patients with gMG, the time to maximal weakness usually is within the first 3 years of disease onset. Accordingly, half of the disease-related mortality also occurs during this period, after which a steady state or improvement occurs. Younger age at onset (< 40 years), early thymectomy, and treatment with corticosteroids have been found to be associated with reduced risk for relapse, and thymectomy results in complete remission of the disease in some patients.

Most affected individuals have a normal lifespan. Morbidity includes quality-of-life issues resulting from muscle weakness, side effects from treatment (long-term effects of corticosteroids used for immunosuppression), and myasthenic crisis (mortality rate, 4.47%). Prognostic factors to be assessed at diagnosis may include:

• Risk for secondary generalization: associated with late age of onset, high AChR antibody titers, thymoma, and presence of both ptosis and diplopia

• Risk for MG relapse: reduced risk for relapse at age < 40 years at onset, early thymectomy, and prednisolone use. Increased risk for relapse with anti-Kv1.4 antibodies and concomitant autoimmune disease.

• Morbidity results from fluctuating impairment of muscle strength, which may result in falls, aspiration, pneumonia, and ventilatory failure.

• Principle risk factors for mortality include age of onset > 40 years, rapid progression of symptoms, and thymoma.

Clinical Takeaway

gMG is an autoimmune disease caused by an antibody-mediated postsynaptic blockade of neuromuscular transmission affecting the acetylcholine receptor. It presents as fatigable muscle weakness, which must be differentiated from other conditions with similar clinical presentations. Decreased muscle strength in patients with gMG can affect quality of life. In severe cases, untreated gMG can lead to myasthenic crisis, a potentially fatal complication due to pneumonia resulting from respiratory muscle weakness. 

Many of the newest therapies, both approved and pending, are targeting specific autoimmune components of the immune system, which are mostly well defined in gMG.

Presentation

A 63-year-old man presented to his primary care provider with ptosis, diplopia, dysphagia, and fatigue/weakness of arms and shoulders after mild activity (eg, raking leaves in his yard, carrying groceries, housework). His ocular symptoms had been present for about 5 months but his arm/shoulder muscle weakness was recent.

Physical examination revealed weakness after repeated/sustained muscle contraction followed by improvement with rest or an ice-pack test (see "Diagnosis" below), and a tentative diagnosis of generalized myasthenia gravis (gMG) was made. The patient was referred to a neurologist for serologic testing, which was positive for anti-AChR MG antibody, confirming the diagnosis of gMG.

Treatment was initiated with pyridostigmine, with reevaluation and treatment escalation as necessary.

gMG is generally defined as a process beginning with localized manifestations of MG, typically ocular muscle involvement. In some patients it remains localized and is considered ocular MG, while in the remaining patients it becomes generalized, most often within 1 year of onset. 

Clinical findings in patients presenting with gMG can include:

• Extraocular muscle weakness (85% of patients) causing diplopia, ptosis, or both

• Bulbar muscle weakness (15% of patients)

  • Difficulty chewing, dysphagia, hoarseness, dysarthria 

  • Facial muscle involvement causing inability to show facial expressions, and neck muscle involvement impairing head posture (dropped-head syndrome)

• Limb weakness

  • Upper limbs more affected than lower

  • Proximal muscles involved more than distal

• Myasthenic crisis, considered a medical emergency due to weakness of the diaphragm and intercostal muscles, secondary to a lower respiratory tract infection

Differential Diagnosis

Several potential diagnoses should be considered on the basis of this patient's presentation.

• Lambert-Eaton myasthenic syndrome: An autoimmune or paraneoplastic disorder producing fluctuating muscle weakness that improves with physical activity, differentiating it from MG

• Cavernous sinus thrombosis: Also called cavernous sinus syndrome, can present with persistent ocular findings, photophobia, chemosis, and headache

• Brainstem gliomas: Can present with dysphagia, muscle weakness, diplopia, drooping eyelids, slurred speech, and/or difficulty breathing

• Multiple sclerosis: Can present with a range of typically fluctuating clinical features, including but not limited to the classic findings of paresthesias, spinal cord and cerebellar symptoms, optic neuritis, diplopia, trigeminal neuralgia, and fatigue

• Botulism: Can present with ptosis, diplopia, difficulty moving the eyes, progressive weakness, and difficulty breathing caused by a toxin produced by Clostridium botulinum

• Tickborne disease: Can present with headache, fatigue, myalgia, rash, and arthralgia, which can mimic the symptoms of other diseases

• Polymyositis/dermatomyositis: Characteristically present with symmetrical proximal muscle weakness, typical rash (dermatomyositis only), elevated serum muscle enzymes, anti-muscle antibodies, and myopathic changes on electromyography

• Graves ophthalmopathy: Also known as thyroid eye disease, can present with photophobia, eye discomfort including gritty eye sensations, lacrimation or dry eye, proptosis, diplopia, and eyelid retraction

• Thyrotoxicosis: Can present with heat intolerance, palpitations, anxiety, fatigue, weight loss, and muscle weakness

Diagnosis

On the basis of this patient's clinical presentation and serology, his diagnosis is generalized AChR MG, class III.

Table. Myasthenia Gravis Foundation of America Clinical Classification 

Commonly performed tests and diagnostic criteria in patients with suspected MG include:

• History/physical examination

• Serology

  • AChR antibody is highly specific (80% positive in gMG, approximately 50% positive in ocular MG)

  • Anti-MUSK antibody (approximately 20% positive, typically in patients negative for AChR antibody)

  • Anti-LRP4 antibody, in patients negative for anti-AChR or anti-MUSK antibody

Detecting established pathogenic antibodies against some synaptic molecules in a patient with clinical features of MG is virtually diagnostic. The presence of AChR antibody confirmed the diagnosis in the case presented above. Although the titer of AChR autoantibodies does not correlate with disease severity, fluctuations in titers in an individual patient have been reported to correlate with the severity of muscle weakness and to predict exacerbations. Accordingly, serial testing for AChR autoantibodies can influence therapeutic decisions.

• Electrodiagnostic studies (useful in patients with negative serology)

  • Repetitive nerve stimulation 

  • Single-fiber electromyography 

• Tests to help confirm that ocular symptoms are due to MG in the absence of positive serology

  • Edrophonium (Tensilon) test: Can induce dramatic but only short-term recovery from symptoms (particularly ocular symptoms)

  • Ice-pack test: Used mainly in ocular MG, in which it can temporarily improve ptosis

• Chest CT/MRI, to screen for thymoma in patients with MG

• Laboratory tests to screen for other autoimmune diseases, including rheumatoid arthritis (rheumatoid factor), systemic lupus erythematosus (ANA), and thyroid eye disease (anti-thyroid antibodies), which may occur concomitantly with MG

Management

The most recent recommendations for management of MG were published in 2021, updating the 2016 International Consensus Guidance for Management of Myasthenia Gravis by the Myasthenia Gravis Foundation of America.

MG can be managed pharmacologically and nonpharmacologically. Pharmacologic treatment includes acetylcholinesterase inhibitors, biologics, and immunosuppressive/immunomodulatory agents. Corticosteroids are used primarily in patients with clinically significant, severe muscle weakness and/or poor response to acetylcholinesterase inhibitors (pyridostigmine).

• Pharmacotherapy

  • Acetylcholinesterase inhibitors

    • Pyridostigmine, an acetylcholinesterase inhibitor used for symptomatic treatment and maintenance therapy, is the only agent in this class used routinely in the clinical setting of MG

  • Biologics

    • Rituximab, a chimeric CD20-directed cytolytic antibody that mediates lysis of B lymphocytes

    • Eculizumab, a humanized monoclonal antibody that specifically binds to the complement protein C5 with high affinity, preventing formation of membrane attack protein (MAC) 

    • Rozanolixizumab, a neonatal Fc receptor blocker that decreases circulating IgG

    • Ravulizumab, a terminal complement inhibitor that specifically binds to complement C5, preventing MAC formation

    • Efgartigimod alfa injection, a neonatal Fc receptor blocker that decreases circulating IgG, with or without hyaluronidase, which increases permeability of subcutaneous tissue by depolymerizing hyaluronan

    • Zilucoplan, a complement protein C5 inhibitor that inhibits its cleavage to C5a and C5b, preventing the generation of the terminal complement complex, C5b-9

  • Immunosuppressive/immunomodulatory agents

    • Tacrolimus, a calcineurin inhibitor

    • Methotrexate, a dihydrofolate reductase inhibitor

    • Cyclosporine, a P-glycoprotein inhibitor and calcineurin inhibitor that also inhibits cytochrome P450 3A4

• Nonpharmacologic therapy

  • Thymectomy, to eliminate a major source of B and T lymphocytes and plasma cells, which produce anti-AChR antibody

  • PLEX (plasmapheresis; plasma exchange), to remove autoantibodies from the circulation

  • IVIg (intravenous immune globulin), recommended perioperatively to stabilize a patient and for management of myasthenic crises because of its rapid onset of action

Prognosis

In patients with gMG, the time to maximal weakness usually is within the first 3 years of disease onset. Accordingly, half of the disease-related mortality also occurs during this period, after which a steady state or improvement occurs. Younger age at onset (< 40 years), early thymectomy, and treatment with corticosteroids have been found to be associated with reduced risk for relapse, and thymectomy results in complete remission of the disease in some patients.

Most affected individuals have a normal lifespan. Morbidity includes quality-of-life issues resulting from muscle weakness, side effects from treatment (long-term effects of corticosteroids used for immunosuppression), and myasthenic crisis (mortality rate, 4.47%). Prognostic factors to be assessed at diagnosis may include:

• Risk for secondary generalization: associated with late age of onset, high AChR antibody titers, thymoma, and presence of both ptosis and diplopia

• Risk for MG relapse: reduced risk for relapse at age < 40 years at onset, early thymectomy, and prednisolone use. Increased risk for relapse with anti-Kv1.4 antibodies and concomitant autoimmune disease.

• Morbidity results from fluctuating impairment of muscle strength, which may result in falls, aspiration, pneumonia, and ventilatory failure.

• Principle risk factors for mortality include age of onset > 40 years, rapid progression of symptoms, and thymoma.

Clinical Takeaway

gMG is an autoimmune disease caused by an antibody-mediated postsynaptic blockade of neuromuscular transmission affecting the acetylcholine receptor. It presents as fatigable muscle weakness, which must be differentiated from other conditions with similar clinical presentations. Decreased muscle strength in patients with gMG can affect quality of life. In severe cases, untreated gMG can lead to myasthenic crisis, a potentially fatal complication due to pneumonia resulting from respiratory muscle weakness. 

Many of the newest therapies, both approved and pending, are targeting specific autoimmune components of the immune system, which are mostly well defined in gMG.

Circulating tumor DNA (ctDNA) testing may serve as an early predictor of response to radiotherapy or chemoradiotherapy in patients with gynecologic cancers, results of a small study suggest.

Among 15 patients with vulvar, cervical, or endometrial malignancies who had serum ctDNA draws prior to, during, and after radiation therapy (RT) or chemoradiotherapy (CRT), both persistence or clearance of residual ctDNA were prognostic of patient outcomes from 3 to 6 months after the end of radiation therapy, reported A. Gabriella Wernicke, MD, MSc, a radiation oncologist at Lenox Hill Hospital in New York City.

“Our early findings in this limited cohort suggest that a mid-treatment ctDNA draw identified responders to radiation, and that may potentially serve as an early predictive biomarker of response. And clearly, these findings need to be validated in a prospective manner, a trial which will be starting in our center soon,” she said in an oral abstract session at the Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer, held in San Diego, California.

Gynecologic malignancies are challenging to manage with radiotherapy because of the treatment’s toxicities and because outcomes may not be known until several months after the end of therapy. Early identification of responses to radiation therapy with simple blood draws has the potential to help clinicians identify those patients whose tumors are responding to radiation early in the course of therapy, she said.
 

Correlating treatment with responses

Dr. Wernicke and colleagues tested their hypothesis that the ctDNA is predictive of treatment response in patients receiving RT or CRT by retrospectively assessing the correlation of clinical responses to ctDNA detection and dynamics.

Their sample included 15 women with vulvar, cervical, or recurrent endometrial cancer who were treated with RT or CRT in 2022 and 2023.

The samples were collected prior to radiation therapy, mid-treatment, prior to boost dose with brachytherapy or stereotactic body radiation therapy, at the end of treatment, and at follow-up at 1, 3, and 6 months after the end of therapy and every 6 months thereafter.

The ctDNA analysis was performed with a personalized assay consisting of multiplex polymerase chain reaction and next-generation sequencing. The assays assessed clonal mutations found in the tumors of each patient.

Of the 15 patients, 5 had vulvar/vaginal tumors, all of squamous cell carcinoma histology. Six patients had squamous cell carcinoma of the cervix, and one had neuroendocrine cervical tumors. The two remaining patients had recurrent endometrial adenocarcinomas.

Eight of the patients had stage III disease, four had stage I or II, one had stage IV, and two had recurrent disease.
 

Results

At baseline 13 of the patients had detectable ctDNA, measured as greater than 0.00 mean tumor molecules per milliliter of plasma (MTM/mL).

There was a strong correlation between elevated ctDNA and measurable disease evaluated by standardized uptake values (SUV) on imaging pre treatment (correlation coefficient = 0.87, P less than .0001).

All patients had reductions in ctDNA from baseline to post-RT/CRT, with 2 having a reduction (partial metabolic response) and 13 having undetectable ctDNA (complete metabolic response) at the end of RT/CRT.

From the mid-treatment blood draw to the posttreatment draw 33% of patients had a partial metabolic response, and 67% had a complete response.

Reduction or clearance of ctDNA also correlated with a decrease in disease burden on MRI during the pre-boost phase of RT.

“Patients with undetectable ctDNA, meaning a complete metabolic response, at mid-radiation and at the end of radiation continued to be clinically without evidence of disease and with undetectable ctDNA at follow-up,” Dr. Wernicke said.

In contrast, the two patients who had partial metabolic responses had disease progression at the end of treatment. Dr. Wernicke noted that one of these patients, who was treated for a neuroendocrine carcinoma of the cervix and had undergone both systemic therapy and CRT, was found to have disease metastatic to the liver and lungs at the 3-month follow-up.
 

How to Use It?

Invited discussant Casey M. Cosgrove, MD, a gynecologic oncologist at Ohio State University Comprehensive Cancer Centers facility in Hilliard, Ohio, said that the reduction of ctDNA levels in all patients was “great,” but the question remains about how the information from ctDNA might be used to guide care in patients undergoing radiation therapy.

“The main questions I have are: If I don’t clear the ctDNA do I need to do more therapy? If I do clear does that mean I need to do less therapy? And if I have negative ctDNA to start what do I do?” he said.

The answers will be found only with further prospective studies, he emphasized.

“These technologies are only going to get better, and better, and better, and this is going to be a conversation that our patients are going to be bringing up, and this is going to be technology that we’re going to be using in our clinics in the very near future,” he added.

Session comoderator Michael Bookman, MD, a gynecology oncologist at Kaiser Permanente in San Francisco, said “it’s worth remembering that FDA approval of a diagnostic test can be obtained prior to showing any clinical benefit. So these are tests that measure what they say they’re measuring, but they haven’t been validated as improving clinical outcomes, which is the task that clearly lies ahead of us.”

The study was internally funded. Dr. Wernicke reported no relevant disclosures. Dr. Cosgrove reported a consulting or advisory role for Intuitive Ltd., GlaxoSmithKline, AstraZeneca, ImmunoGen, and Merck, and research fees from GSK. Dr. Bookman reported clinical trial advising/monitoring for Immunogen and Clovis Oncology, with fees paid to his institution.

Circulating tumor DNA (ctDNA) testing may serve as an early predictor of response to radiotherapy or chemoradiotherapy in patients with gynecologic cancers, results of a small study suggest.

Among 15 patients with vulvar, cervical, or endometrial malignancies who had serum ctDNA draws prior to, during, and after radiation therapy (RT) or chemoradiotherapy (CRT), both persistence or clearance of residual ctDNA were prognostic of patient outcomes from 3 to 6 months after the end of radiation therapy, reported A. Gabriella Wernicke, MD, MSc, a radiation oncologist at Lenox Hill Hospital in New York City.

“Our early findings in this limited cohort suggest that a mid-treatment ctDNA draw identified responders to radiation, and that may potentially serve as an early predictive biomarker of response. And clearly, these findings need to be validated in a prospective manner, a trial which will be starting in our center soon,” she said in an oral abstract session at the Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer, held in San Diego, California.

Gynecologic malignancies are challenging to manage with radiotherapy because of the treatment’s toxicities and because outcomes may not be known until several months after the end of therapy. Early identification of responses to radiation therapy with simple blood draws has the potential to help clinicians identify those patients whose tumors are responding to radiation early in the course of therapy, she said.
 

Correlating treatment with responses

Dr. Wernicke and colleagues tested their hypothesis that the ctDNA is predictive of treatment response in patients receiving RT or CRT by retrospectively assessing the correlation of clinical responses to ctDNA detection and dynamics.

Their sample included 15 women with vulvar, cervical, or recurrent endometrial cancer who were treated with RT or CRT in 2022 and 2023.

The samples were collected prior to radiation therapy, mid-treatment, prior to boost dose with brachytherapy or stereotactic body radiation therapy, at the end of treatment, and at follow-up at 1, 3, and 6 months after the end of therapy and every 6 months thereafter.

The ctDNA analysis was performed with a personalized assay consisting of multiplex polymerase chain reaction and next-generation sequencing. The assays assessed clonal mutations found in the tumors of each patient.

Of the 15 patients, 5 had vulvar/vaginal tumors, all of squamous cell carcinoma histology. Six patients had squamous cell carcinoma of the cervix, and one had neuroendocrine cervical tumors. The two remaining patients had recurrent endometrial adenocarcinomas.

Eight of the patients had stage III disease, four had stage I or II, one had stage IV, and two had recurrent disease.
 

Results

At baseline 13 of the patients had detectable ctDNA, measured as greater than 0.00 mean tumor molecules per milliliter of plasma (MTM/mL).

There was a strong correlation between elevated ctDNA and measurable disease evaluated by standardized uptake values (SUV) on imaging pre treatment (correlation coefficient = 0.87, P less than .0001).

All patients had reductions in ctDNA from baseline to post-RT/CRT, with 2 having a reduction (partial metabolic response) and 13 having undetectable ctDNA (complete metabolic response) at the end of RT/CRT.

From the mid-treatment blood draw to the posttreatment draw 33% of patients had a partial metabolic response, and 67% had a complete response.

Reduction or clearance of ctDNA also correlated with a decrease in disease burden on MRI during the pre-boost phase of RT.

“Patients with undetectable ctDNA, meaning a complete metabolic response, at mid-radiation and at the end of radiation continued to be clinically without evidence of disease and with undetectable ctDNA at follow-up,” Dr. Wernicke said.

In contrast, the two patients who had partial metabolic responses had disease progression at the end of treatment. Dr. Wernicke noted that one of these patients, who was treated for a neuroendocrine carcinoma of the cervix and had undergone both systemic therapy and CRT, was found to have disease metastatic to the liver and lungs at the 3-month follow-up.
 

How to Use It?

Invited discussant Casey M. Cosgrove, MD, a gynecologic oncologist at Ohio State University Comprehensive Cancer Centers facility in Hilliard, Ohio, said that the reduction of ctDNA levels in all patients was “great,” but the question remains about how the information from ctDNA might be used to guide care in patients undergoing radiation therapy.

“The main questions I have are: If I don’t clear the ctDNA do I need to do more therapy? If I do clear does that mean I need to do less therapy? And if I have negative ctDNA to start what do I do?” he said.

The answers will be found only with further prospective studies, he emphasized.

“These technologies are only going to get better, and better, and better, and this is going to be a conversation that our patients are going to be bringing up, and this is going to be technology that we’re going to be using in our clinics in the very near future,” he added.

Session comoderator Michael Bookman, MD, a gynecology oncologist at Kaiser Permanente in San Francisco, said “it’s worth remembering that FDA approval of a diagnostic test can be obtained prior to showing any clinical benefit. So these are tests that measure what they say they’re measuring, but they haven’t been validated as improving clinical outcomes, which is the task that clearly lies ahead of us.”

The study was internally funded. Dr. Wernicke reported no relevant disclosures. Dr. Cosgrove reported a consulting or advisory role for Intuitive Ltd., GlaxoSmithKline, AstraZeneca, ImmunoGen, and Merck, and research fees from GSK. Dr. Bookman reported clinical trial advising/monitoring for Immunogen and Clovis Oncology, with fees paid to his institution.

Circulating tumor DNA (ctDNA) testing may serve as an early predictor of response to radiotherapy or chemoradiotherapy in patients with gynecologic cancers, results of a small study suggest.

Among 15 patients with vulvar, cervical, or endometrial malignancies who had serum ctDNA draws prior to, during, and after radiation therapy (RT) or chemoradiotherapy (CRT), both persistence or clearance of residual ctDNA were prognostic of patient outcomes from 3 to 6 months after the end of radiation therapy, reported A. Gabriella Wernicke, MD, MSc, a radiation oncologist at Lenox Hill Hospital in New York City.

“Our early findings in this limited cohort suggest that a mid-treatment ctDNA draw identified responders to radiation, and that may potentially serve as an early predictive biomarker of response. And clearly, these findings need to be validated in a prospective manner, a trial which will be starting in our center soon,” she said in an oral abstract session at the Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer, held in San Diego, California.

Gynecologic malignancies are challenging to manage with radiotherapy because of the treatment’s toxicities and because outcomes may not be known until several months after the end of therapy. Early identification of responses to radiation therapy with simple blood draws has the potential to help clinicians identify those patients whose tumors are responding to radiation early in the course of therapy, she said.
 

Correlating treatment with responses

Dr. Wernicke and colleagues tested their hypothesis that the ctDNA is predictive of treatment response in patients receiving RT or CRT by retrospectively assessing the correlation of clinical responses to ctDNA detection and dynamics.

Their sample included 15 women with vulvar, cervical, or recurrent endometrial cancer who were treated with RT or CRT in 2022 and 2023.

The samples were collected prior to radiation therapy, mid-treatment, prior to boost dose with brachytherapy or stereotactic body radiation therapy, at the end of treatment, and at follow-up at 1, 3, and 6 months after the end of therapy and every 6 months thereafter.

The ctDNA analysis was performed with a personalized assay consisting of multiplex polymerase chain reaction and next-generation sequencing. The assays assessed clonal mutations found in the tumors of each patient.

Of the 15 patients, 5 had vulvar/vaginal tumors, all of squamous cell carcinoma histology. Six patients had squamous cell carcinoma of the cervix, and one had neuroendocrine cervical tumors. The two remaining patients had recurrent endometrial adenocarcinomas.

Eight of the patients had stage III disease, four had stage I or II, one had stage IV, and two had recurrent disease.
 

Results

At baseline 13 of the patients had detectable ctDNA, measured as greater than 0.00 mean tumor molecules per milliliter of plasma (MTM/mL).

There was a strong correlation between elevated ctDNA and measurable disease evaluated by standardized uptake values (SUV) on imaging pre treatment (correlation coefficient = 0.87, P less than .0001).

All patients had reductions in ctDNA from baseline to post-RT/CRT, with 2 having a reduction (partial metabolic response) and 13 having undetectable ctDNA (complete metabolic response) at the end of RT/CRT.

From the mid-treatment blood draw to the posttreatment draw 33% of patients had a partial metabolic response, and 67% had a complete response.

Reduction or clearance of ctDNA also correlated with a decrease in disease burden on MRI during the pre-boost phase of RT.

“Patients with undetectable ctDNA, meaning a complete metabolic response, at mid-radiation and at the end of radiation continued to be clinically without evidence of disease and with undetectable ctDNA at follow-up,” Dr. Wernicke said.

In contrast, the two patients who had partial metabolic responses had disease progression at the end of treatment. Dr. Wernicke noted that one of these patients, who was treated for a neuroendocrine carcinoma of the cervix and had undergone both systemic therapy and CRT, was found to have disease metastatic to the liver and lungs at the 3-month follow-up.
 

How to Use It?

Invited discussant Casey M. Cosgrove, MD, a gynecologic oncologist at Ohio State University Comprehensive Cancer Centers facility in Hilliard, Ohio, said that the reduction of ctDNA levels in all patients was “great,” but the question remains about how the information from ctDNA might be used to guide care in patients undergoing radiation therapy.

“The main questions I have are: If I don’t clear the ctDNA do I need to do more therapy? If I do clear does that mean I need to do less therapy? And if I have negative ctDNA to start what do I do?” he said.

The answers will be found only with further prospective studies, he emphasized.

“These technologies are only going to get better, and better, and better, and this is going to be a conversation that our patients are going to be bringing up, and this is going to be technology that we’re going to be using in our clinics in the very near future,” he added.

Session comoderator Michael Bookman, MD, a gynecology oncologist at Kaiser Permanente in San Francisco, said “it’s worth remembering that FDA approval of a diagnostic test can be obtained prior to showing any clinical benefit. So these are tests that measure what they say they’re measuring, but they haven’t been validated as improving clinical outcomes, which is the task that clearly lies ahead of us.”

The study was internally funded. Dr. Wernicke reported no relevant disclosures. Dr. Cosgrove reported a consulting or advisory role for Intuitive Ltd., GlaxoSmithKline, AstraZeneca, ImmunoGen, and Merck, and research fees from GSK. Dr. Bookman reported clinical trial advising/monitoring for Immunogen and Clovis Oncology, with fees paid to his institution.

A new study raises a cautionary note on time-restricted eating (TRE), a type of intermittent fasting that is gaining popularity.

The observational analysis of over 20,000 US adults showed that those who limited their eating to a period of less than 8 hours per day had a higher risk for cardiovascular mortality compared with peers who ate across the typical 12-16 hours per day. This was the case in the overall sample and in those with cardiovascular disease (CVD) or cancer.

Lead author Victor Wenze Zhong, PhD, cautioned that the findings “require replication and we cannot demonstrate 8-hour TRE causes cardiovascular death in this observational study.

“However, it’s important for patients, particularly those with existing heart conditions or cancer, to be aware of the positive association between an 8-hour eating window and cardiovascular death,” Dr. Zhong, professor and chair, Department of Epidemiology and Biostatistics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China, told this news organization. 

The results (Abstract P192) were presented March 18 at the American Heart Association (AHA) Epidemiology and Prevention/Lifestyle and Cardiometabolic Health Scientific Sessions 2024.
 

‘Provocative’ Results 

Short-term randomized controlled trials have suggested that 8-hour TRE may improve cardiometabolic risk profiles, but the potential long-term effects of this eating pattern are unknown. 

The observation that TRE may have short-term benefits but long-term adverse effects is “interesting and provocative” and needs further study, Christopher D. Gardner, PhD, professor of medicine at Stanford University in California, who wasn’t involved in the study, said in a conference statement, and he agreed that much more research is needed. 

The researchers analyzed data on dietary patterns for 20,078 adults (mean age, 48 years; 50% men; 73% non-Hispanic White) who participated in the 2003-2018 National Health and Nutrition Examination Surveys (NHANES). All of them completed two 24-hour dietary recall questionnaires within the first year of enrollment. Deaths through the end of 2019 were determined via the National Death Index.

During a median follow-up of 8 years, there were 2797 deaths due to any cause, including 840 CV deaths and 643 cancer deaths. 

In the overall sample, compared with an eating duration of 12-16 hours, 8-hour TRE was significantly associated with an increased risk for CV mortality (hazard ratio [HR], 1.91; 95% CI, 1.20-3.03).

This association was also observed in adults with CVD (HR, 2.07; 95% CI, 1.14-3.78) and adults with cancer (HR, 3.04; 95% CI, 1.44-6.41). 

Other eating durations were not associated with CV mortality, except for eating duration of 8 to less than 10 hours in people with CVD (HR, 1.66; 95% CI, 1.03-2.67). 

No significant associations were found between eating duration and all-cause or cancer mortality in the overall sample and CVD/cancer subsamples, except that eating duration of more than 16 hours was associated with a lower risk for cancer mortality in people with cancer (HR, 0.47; 95% CI, 0.23-0.95).
 

Quality More Important Than Timing 

Dr. Zhong noted that the study doesn’t address the underlying mechanisms driving the observed association between 8-hour TRE and CV death. 

“However, we did observe that people who restricted eating to a period less than 8 hours per day had less lean muscle mass compared with those with typical eating duration of 12-16 hours. Loss of lean body mass has been linked to higher risk of cardiovascular mortality,” Dr. Zhong said. 

“Based on the evidence as of now, focusing on what people eat appears to be more important than focusing on the time when they eat. There are certain dietary approaches with compelling health benefits to choose, such as DASH diet and Mediterranean diet,” Dr. Zhong said.

Intermittent fasting is “certainly an interesting concept and one on which the potential mechanisms underlying the improvements in short outcome studies and preclinical studies in animals are strongly being pursued,” Sean P. Heffron, MD, cardiologist at the Center for the Prevention of Cardiovascular Disease at NYU Langone Heart, New York, who wasn’t involved in the study, told this news organization. 

Dr. Heffron expressed skepticism about the study results calling them “far from complete” and noted that data on diet was based on only 2-day diet records without correction for confounding variables. 

Dr. Heffron also noted that the restricted diet group has more smokers and more men. “I would “strongly anticipate that once appropriate corrections are made, the findings will no longer persist in statistical significance,” Dr. Heffron said.

He emphasized the need for more rigorous research before making clinical recommendations. When patients ask about intermittent fasting, Dr. Heffron said he tells them, “If it works for you, that’s fine,” but he doesn’t provide a recommendation for or against it. 

Funding for the study was provided by the National Key Research and Development Program of China and the National Science Foundation of China. Zhong, Dr. Heffron and Dr. Gardner have no relevant disclosures.
 

A version of this article appeared on Medscape.com.

A new study raises a cautionary note on time-restricted eating (TRE), a type of intermittent fasting that is gaining popularity.

The observational analysis of over 20,000 US adults showed that those who limited their eating to a period of less than 8 hours per day had a higher risk for cardiovascular mortality compared with peers who ate across the typical 12-16 hours per day. This was the case in the overall sample and in those with cardiovascular disease (CVD) or cancer.

Lead author Victor Wenze Zhong, PhD, cautioned that the findings “require replication and we cannot demonstrate 8-hour TRE causes cardiovascular death in this observational study.

“However, it’s important for patients, particularly those with existing heart conditions or cancer, to be aware of the positive association between an 8-hour eating window and cardiovascular death,” Dr. Zhong, professor and chair, Department of Epidemiology and Biostatistics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China, told this news organization. 

The results (Abstract P192) were presented March 18 at the American Heart Association (AHA) Epidemiology and Prevention/Lifestyle and Cardiometabolic Health Scientific Sessions 2024.
 

‘Provocative’ Results 

Short-term randomized controlled trials have suggested that 8-hour TRE may improve cardiometabolic risk profiles, but the potential long-term effects of this eating pattern are unknown. 

The observation that TRE may have short-term benefits but long-term adverse effects is “interesting and provocative” and needs further study, Christopher D. Gardner, PhD, professor of medicine at Stanford University in California, who wasn’t involved in the study, said in a conference statement, and he agreed that much more research is needed. 

The researchers analyzed data on dietary patterns for 20,078 adults (mean age, 48 years; 50% men; 73% non-Hispanic White) who participated in the 2003-2018 National Health and Nutrition Examination Surveys (NHANES). All of them completed two 24-hour dietary recall questionnaires within the first year of enrollment. Deaths through the end of 2019 were determined via the National Death Index.

During a median follow-up of 8 years, there were 2797 deaths due to any cause, including 840 CV deaths and 643 cancer deaths. 

In the overall sample, compared with an eating duration of 12-16 hours, 8-hour TRE was significantly associated with an increased risk for CV mortality (hazard ratio [HR], 1.91; 95% CI, 1.20-3.03).

This association was also observed in adults with CVD (HR, 2.07; 95% CI, 1.14-3.78) and adults with cancer (HR, 3.04; 95% CI, 1.44-6.41). 

Other eating durations were not associated with CV mortality, except for eating duration of 8 to less than 10 hours in people with CVD (HR, 1.66; 95% CI, 1.03-2.67). 

No significant associations were found between eating duration and all-cause or cancer mortality in the overall sample and CVD/cancer subsamples, except that eating duration of more than 16 hours was associated with a lower risk for cancer mortality in people with cancer (HR, 0.47; 95% CI, 0.23-0.95).
 

Quality More Important Than Timing 

Dr. Zhong noted that the study doesn’t address the underlying mechanisms driving the observed association between 8-hour TRE and CV death. 

“However, we did observe that people who restricted eating to a period less than 8 hours per day had less lean muscle mass compared with those with typical eating duration of 12-16 hours. Loss of lean body mass has been linked to higher risk of cardiovascular mortality,” Dr. Zhong said. 

“Based on the evidence as of now, focusing on what people eat appears to be more important than focusing on the time when they eat. There are certain dietary approaches with compelling health benefits to choose, such as DASH diet and Mediterranean diet,” Dr. Zhong said.

Intermittent fasting is “certainly an interesting concept and one on which the potential mechanisms underlying the improvements in short outcome studies and preclinical studies in animals are strongly being pursued,” Sean P. Heffron, MD, cardiologist at the Center for the Prevention of Cardiovascular Disease at NYU Langone Heart, New York, who wasn’t involved in the study, told this news organization. 

Dr. Heffron expressed skepticism about the study results calling them “far from complete” and noted that data on diet was based on only 2-day diet records without correction for confounding variables. 

Dr. Heffron also noted that the restricted diet group has more smokers and more men. “I would “strongly anticipate that once appropriate corrections are made, the findings will no longer persist in statistical significance,” Dr. Heffron said.

He emphasized the need for more rigorous research before making clinical recommendations. When patients ask about intermittent fasting, Dr. Heffron said he tells them, “If it works for you, that’s fine,” but he doesn’t provide a recommendation for or against it. 

Funding for the study was provided by the National Key Research and Development Program of China and the National Science Foundation of China. Zhong, Dr. Heffron and Dr. Gardner have no relevant disclosures.
 

A version of this article appeared on Medscape.com.

A new study raises a cautionary note on time-restricted eating (TRE), a type of intermittent fasting that is gaining popularity.

The observational analysis of over 20,000 US adults showed that those who limited their eating to a period of less than 8 hours per day had a higher risk for cardiovascular mortality compared with peers who ate across the typical 12-16 hours per day. This was the case in the overall sample and in those with cardiovascular disease (CVD) or cancer.

Lead author Victor Wenze Zhong, PhD, cautioned that the findings “require replication and we cannot demonstrate 8-hour TRE causes cardiovascular death in this observational study.

“However, it’s important for patients, particularly those with existing heart conditions or cancer, to be aware of the positive association between an 8-hour eating window and cardiovascular death,” Dr. Zhong, professor and chair, Department of Epidemiology and Biostatistics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China, told this news organization. 

The results (Abstract P192) were presented March 18 at the American Heart Association (AHA) Epidemiology and Prevention/Lifestyle and Cardiometabolic Health Scientific Sessions 2024.
 

‘Provocative’ Results 

Short-term randomized controlled trials have suggested that 8-hour TRE may improve cardiometabolic risk profiles, but the potential long-term effects of this eating pattern are unknown. 

The observation that TRE may have short-term benefits but long-term adverse effects is “interesting and provocative” and needs further study, Christopher D. Gardner, PhD, professor of medicine at Stanford University in California, who wasn’t involved in the study, said in a conference statement, and he agreed that much more research is needed. 

The researchers analyzed data on dietary patterns for 20,078 adults (mean age, 48 years; 50% men; 73% non-Hispanic White) who participated in the 2003-2018 National Health and Nutrition Examination Surveys (NHANES). All of them completed two 24-hour dietary recall questionnaires within the first year of enrollment. Deaths through the end of 2019 were determined via the National Death Index.

During a median follow-up of 8 years, there were 2797 deaths due to any cause, including 840 CV deaths and 643 cancer deaths. 

In the overall sample, compared with an eating duration of 12-16 hours, 8-hour TRE was significantly associated with an increased risk for CV mortality (hazard ratio [HR], 1.91; 95% CI, 1.20-3.03).

This association was also observed in adults with CVD (HR, 2.07; 95% CI, 1.14-3.78) and adults with cancer (HR, 3.04; 95% CI, 1.44-6.41). 

Other eating durations were not associated with CV mortality, except for eating duration of 8 to less than 10 hours in people with CVD (HR, 1.66; 95% CI, 1.03-2.67). 

No significant associations were found between eating duration and all-cause or cancer mortality in the overall sample and CVD/cancer subsamples, except that eating duration of more than 16 hours was associated with a lower risk for cancer mortality in people with cancer (HR, 0.47; 95% CI, 0.23-0.95).
 

Quality More Important Than Timing 

Dr. Zhong noted that the study doesn’t address the underlying mechanisms driving the observed association between 8-hour TRE and CV death. 

“However, we did observe that people who restricted eating to a period less than 8 hours per day had less lean muscle mass compared with those with typical eating duration of 12-16 hours. Loss of lean body mass has been linked to higher risk of cardiovascular mortality,” Dr. Zhong said. 

“Based on the evidence as of now, focusing on what people eat appears to be more important than focusing on the time when they eat. There are certain dietary approaches with compelling health benefits to choose, such as DASH diet and Mediterranean diet,” Dr. Zhong said.

Intermittent fasting is “certainly an interesting concept and one on which the potential mechanisms underlying the improvements in short outcome studies and preclinical studies in animals are strongly being pursued,” Sean P. Heffron, MD, cardiologist at the Center for the Prevention of Cardiovascular Disease at NYU Langone Heart, New York, who wasn’t involved in the study, told this news organization. 

Dr. Heffron expressed skepticism about the study results calling them “far from complete” and noted that data on diet was based on only 2-day diet records without correction for confounding variables. 

Dr. Heffron also noted that the restricted diet group has more smokers and more men. “I would “strongly anticipate that once appropriate corrections are made, the findings will no longer persist in statistical significance,” Dr. Heffron said.

He emphasized the need for more rigorous research before making clinical recommendations. When patients ask about intermittent fasting, Dr. Heffron said he tells them, “If it works for you, that’s fine,” but he doesn’t provide a recommendation for or against it. 

Funding for the study was provided by the National Key Research and Development Program of China and the National Science Foundation of China. Zhong, Dr. Heffron and Dr. Gardner have no relevant disclosures.
 

A version of this article appeared on Medscape.com.

This transcript has been edited for clarity.

Rachel S. Rubin, MD: We are here at the Harvard Continuing Medical Education Course in Orlando, Florida. It’s all about testosterone therapy and sexual medicine. I have with me today the wonderful Dr. Marianne Brandon, who is an amazing sex therapist. Could you introduce yourself?

Marianne Brandon, PhD: I am a clinical psychologist and sex therapist. I’ve been in practice for more than 25 years. I’m currently located in Sarasota. I have a Psychology Today blog called The Future of Intimacy, which I have a lot of fun with.

Dr. Rubin: It’s very important, when taking care of patients, that we work in a biopsychosocial model. Yes, we can fix erectile dysfunction. We can help with menopause symptoms and that helps sexual function. But what I find makes my patients able to live their best lives is when they have a team, including a mental health professional — often a sex therapist or a couples’ therapist — where they can learn communication skills. Why is it important for primary care doctors to talk to their patients about sex? My primary care doctor has never asked me about sex.  

Dr. Brandon: For most people, sexual intimacy is critical for their experience of life. It correlates with their relationship satisfaction and life satisfaction. It’s much bigger than what’s happening in the bedroom. People have more struggles than you realize. Sexual dysfunction correlates with emotional issues such as depression and anxiety, with medical problems, and with medication use. Chances are that your patients have some kind of sexual concern, even if that’s not to the degree that it would be classified as a sexual dysfunction.

But sexual concerns wreak havoc. Believing they have a sexual problem, they stop touching, they stop relating to their partner. It becomes a really big deal in their lives. If you can open the door for a conversation about sex with your patients, it could do them a great deal of good. It’s also good for the practitioner, because if your patients think they can talk with you about anything, that’s going to establish your relationship with them. Practitioners avoid these conversations because they don’t have the time or the training to offer help.

Dr. Rubin: You don’t have to know all the answers. You just have to show empathy and compassion and say, “I hear you.” That’s the magic in the doctor-patient relationship. We refer patients to specialists when we don’t know what to do. What happens when I send a patient to a sex therapist? Do they watch them have sex? Of course not, but everyone thinks that is what sex therapists do.

Dr. Brandon: Sex therapy is just like any other type of therapy, but we discuss sexual issues. And because just about anything that’s happening in your patient’s life can trickle down into the bedroom, we end up talking about a lot of stuff that’s not directly related to sex but ultimately impacts the patient’s sex life.

Dr. Rubin: It’s true. Most medical conditions that we treat — from diabetes, hypertension, high cholesterol, and obesity to depression and anxiety — are strongly correlated with sexual health. We treat the underlying condition, but our patients don’t care about their A1c levels. They care about the fact that they cannot get aroused; their genitals don’t feel the same way they used to.

Dr. Brandon: I love that point because people make meaning out of their sexual concerns and dysfunction. Suddenly their body isn’t responding the way it used to. They think something’s wrong with them, or maybe they are with the wrong partner. This meaning becomes very powerful in their mind and perpetuates the sexual problem.

Dr. Rubin: First and foremost, we are educators. We can say, “You have pretty out-of-control diabetes,” or, “You’re a smoker, which can affect the health of your genitals. Have you noticed any issues going on there?” If you don’t ask, patients will not bring up their concerns with their doctors.

So how do people find a sex therapist?

Dr. Brandon: There are a few fabulous organizations that provide on their websites ways to find a therapist: the American Association of Sex Educators, Counselors and Therapists (AASECT) and Sex Therapy and Research (STAR). Giving patients this information is a huge intervention.

Other places to find a therapist include the International Society for Sexual Medicine, and the International Society for the Study of Women’s Sexual Health.

Since COVID, many therapists have gone virtual. Encourage your patients to look within their states to find options for therapists and psychologists. Recent legislation allows psychologists who have signed up for PSYPACT to practice almost throughout the entire United States. We used to think if we didn’t have a therapist in the community, we couldn’t make a referral. That›s not the case anymore.

Dr. Rubin: All doctors are really sexual medicine doctors. We can change the whole world by giving our patients a better quality of life.
 

Dr. Rubin, Assistant Clinical Professor, Department of Urology, Georgetown University, Washington, disclosed ties to Sprout, Maternal Medical, Absorption Pharmaceuticals, GlaxoSmithKline, and Endo.

A version of this article appeared on Medscape.com.

This transcript has been edited for clarity.

Rachel S. Rubin, MD: We are here at the Harvard Continuing Medical Education Course in Orlando, Florida. It’s all about testosterone therapy and sexual medicine. I have with me today the wonderful Dr. Marianne Brandon, who is an amazing sex therapist. Could you introduce yourself?

Marianne Brandon, PhD: I am a clinical psychologist and sex therapist. I’ve been in practice for more than 25 years. I’m currently located in Sarasota. I have a Psychology Today blog called The Future of Intimacy, which I have a lot of fun with.

Dr. Rubin: It’s very important, when taking care of patients, that we work in a biopsychosocial model. Yes, we can fix erectile dysfunction. We can help with menopause symptoms and that helps sexual function. But what I find makes my patients able to live their best lives is when they have a team, including a mental health professional — often a sex therapist or a couples’ therapist — where they can learn communication skills. Why is it important for primary care doctors to talk to their patients about sex? My primary care doctor has never asked me about sex.  

Dr. Brandon: For most people, sexual intimacy is critical for their experience of life. It correlates with their relationship satisfaction and life satisfaction. It’s much bigger than what’s happening in the bedroom. People have more struggles than you realize. Sexual dysfunction correlates with emotional issues such as depression and anxiety, with medical problems, and with medication use. Chances are that your patients have some kind of sexual concern, even if that’s not to the degree that it would be classified as a sexual dysfunction.

But sexual concerns wreak havoc. Believing they have a sexual problem, they stop touching, they stop relating to their partner. It becomes a really big deal in their lives. If you can open the door for a conversation about sex with your patients, it could do them a great deal of good. It’s also good for the practitioner, because if your patients think they can talk with you about anything, that’s going to establish your relationship with them. Practitioners avoid these conversations because they don’t have the time or the training to offer help.

Dr. Rubin: You don’t have to know all the answers. You just have to show empathy and compassion and say, “I hear you.” That’s the magic in the doctor-patient relationship. We refer patients to specialists when we don’t know what to do. What happens when I send a patient to a sex therapist? Do they watch them have sex? Of course not, but everyone thinks that is what sex therapists do.

Dr. Brandon: Sex therapy is just like any other type of therapy, but we discuss sexual issues. And because just about anything that’s happening in your patient’s life can trickle down into the bedroom, we end up talking about a lot of stuff that’s not directly related to sex but ultimately impacts the patient’s sex life.

Dr. Rubin: It’s true. Most medical conditions that we treat — from diabetes, hypertension, high cholesterol, and obesity to depression and anxiety — are strongly correlated with sexual health. We treat the underlying condition, but our patients don’t care about their A1c levels. They care about the fact that they cannot get aroused; their genitals don’t feel the same way they used to.

Dr. Brandon: I love that point because people make meaning out of their sexual concerns and dysfunction. Suddenly their body isn’t responding the way it used to. They think something’s wrong with them, or maybe they are with the wrong partner. This meaning becomes very powerful in their mind and perpetuates the sexual problem.

Dr. Rubin: First and foremost, we are educators. We can say, “You have pretty out-of-control diabetes,” or, “You’re a smoker, which can affect the health of your genitals. Have you noticed any issues going on there?” If you don’t ask, patients will not bring up their concerns with their doctors.

So how do people find a sex therapist?

Dr. Brandon: There are a few fabulous organizations that provide on their websites ways to find a therapist: the American Association of Sex Educators, Counselors and Therapists (AASECT) and Sex Therapy and Research (STAR). Giving patients this information is a huge intervention.

Other places to find a therapist include the International Society for Sexual Medicine, and the International Society for the Study of Women’s Sexual Health.

Since COVID, many therapists have gone virtual. Encourage your patients to look within their states to find options for therapists and psychologists. Recent legislation allows psychologists who have signed up for PSYPACT to practice almost throughout the entire United States. We used to think if we didn’t have a therapist in the community, we couldn’t make a referral. That›s not the case anymore.

Dr. Rubin: All doctors are really sexual medicine doctors. We can change the whole world by giving our patients a better quality of life.
 

Dr. Rubin, Assistant Clinical Professor, Department of Urology, Georgetown University, Washington, disclosed ties to Sprout, Maternal Medical, Absorption Pharmaceuticals, GlaxoSmithKline, and Endo.

A version of this article appeared on Medscape.com.

This transcript has been edited for clarity.

Rachel S. Rubin, MD: We are here at the Harvard Continuing Medical Education Course in Orlando, Florida. It’s all about testosterone therapy and sexual medicine. I have with me today the wonderful Dr. Marianne Brandon, who is an amazing sex therapist. Could you introduce yourself?

Marianne Brandon, PhD: I am a clinical psychologist and sex therapist. I’ve been in practice for more than 25 years. I’m currently located in Sarasota. I have a Psychology Today blog called The Future of Intimacy, which I have a lot of fun with.

Dr. Rubin: It’s very important, when taking care of patients, that we work in a biopsychosocial model. Yes, we can fix erectile dysfunction. We can help with menopause symptoms and that helps sexual function. But what I find makes my patients able to live their best lives is when they have a team, including a mental health professional — often a sex therapist or a couples’ therapist — where they can learn communication skills. Why is it important for primary care doctors to talk to their patients about sex? My primary care doctor has never asked me about sex.  

Dr. Brandon: For most people, sexual intimacy is critical for their experience of life. It correlates with their relationship satisfaction and life satisfaction. It’s much bigger than what’s happening in the bedroom. People have more struggles than you realize. Sexual dysfunction correlates with emotional issues such as depression and anxiety, with medical problems, and with medication use. Chances are that your patients have some kind of sexual concern, even if that’s not to the degree that it would be classified as a sexual dysfunction.

But sexual concerns wreak havoc. Believing they have a sexual problem, they stop touching, they stop relating to their partner. It becomes a really big deal in their lives. If you can open the door for a conversation about sex with your patients, it could do them a great deal of good. It’s also good for the practitioner, because if your patients think they can talk with you about anything, that’s going to establish your relationship with them. Practitioners avoid these conversations because they don’t have the time or the training to offer help.

Dr. Rubin: You don’t have to know all the answers. You just have to show empathy and compassion and say, “I hear you.” That’s the magic in the doctor-patient relationship. We refer patients to specialists when we don’t know what to do. What happens when I send a patient to a sex therapist? Do they watch them have sex? Of course not, but everyone thinks that is what sex therapists do.

Dr. Brandon: Sex therapy is just like any other type of therapy, but we discuss sexual issues. And because just about anything that’s happening in your patient’s life can trickle down into the bedroom, we end up talking about a lot of stuff that’s not directly related to sex but ultimately impacts the patient’s sex life.

Dr. Rubin: It’s true. Most medical conditions that we treat — from diabetes, hypertension, high cholesterol, and obesity to depression and anxiety — are strongly correlated with sexual health. We treat the underlying condition, but our patients don’t care about their A1c levels. They care about the fact that they cannot get aroused; their genitals don’t feel the same way they used to.

Dr. Brandon: I love that point because people make meaning out of their sexual concerns and dysfunction. Suddenly their body isn’t responding the way it used to. They think something’s wrong with them, or maybe they are with the wrong partner. This meaning becomes very powerful in their mind and perpetuates the sexual problem.

Dr. Rubin: First and foremost, we are educators. We can say, “You have pretty out-of-control diabetes,” or, “You’re a smoker, which can affect the health of your genitals. Have you noticed any issues going on there?” If you don’t ask, patients will not bring up their concerns with their doctors.

So how do people find a sex therapist?

Dr. Brandon: There are a few fabulous organizations that provide on their websites ways to find a therapist: the American Association of Sex Educators, Counselors and Therapists (AASECT) and Sex Therapy and Research (STAR). Giving patients this information is a huge intervention.

Other places to find a therapist include the International Society for Sexual Medicine, and the International Society for the Study of Women’s Sexual Health.

Since COVID, many therapists have gone virtual. Encourage your patients to look within their states to find options for therapists and psychologists. Recent legislation allows psychologists who have signed up for PSYPACT to practice almost throughout the entire United States. We used to think if we didn’t have a therapist in the community, we couldn’t make a referral. That›s not the case anymore.

Dr. Rubin: All doctors are really sexual medicine doctors. We can change the whole world by giving our patients a better quality of life.
 

Dr. Rubin, Assistant Clinical Professor, Department of Urology, Georgetown University, Washington, disclosed ties to Sprout, Maternal Medical, Absorption Pharmaceuticals, GlaxoSmithKline, and Endo.

A version of this article appeared on Medscape.com.

TOPLINE:

Secondary cancers were flagged in 4.3% of all adverse event reports among patients who received CAR T therapy, with T-cell malignancies comprising only 0.15% of the total reports and 3.54% of all second primary malignancies, according to an analysis of adverse event reports submitted to the US Food and Drug Administration (FDA).

METHODOLOGY:

• In November 2023, the FDA announced its investigation into whether chimeric antigen receptor (CAR) T-cell immunotherapies can cause secondary blood cancers, specifically T-cell malignancies. At the time, the agency said: “Although the overall benefits of these products continue to outweigh their potential risks for their approved uses, FDA is investigating the identified risk of T-cell malignancy with serious outcomes.”
• In January 2024, the FDA issued boxed warnings on the six approved CART cell therapies, citing the possibility of second primary malignancies, including CAR-positive lymphomas, in patients who had received a CAR T agent.
• To evaluate the extent of these secondary cancers, researchers analyzed the FDA Adverse Event Reporting System database for CAR T-cell reports citing second primary malignancies.

TAKEAWAY:

• Overall, the authors identified 12,394 unique adverse events associated with CAR T therapy; of these, 536 adverse events (4.3%) were second primary malignancies.
• Axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tis-cel) accounted for most of the second primary malignancies reports — 51.7% (277 of 536 patients) for axi-cel and 33% (177 of 536 patients) for tis-cel.
• The researchers identified 19 cases of T-cell malignancies, representing only 0.15% of all unique adverse events and 3.54% of all second primary malignancies (19 of 536 patients); 17 of these cases were T-cell non-Hodgkin lymphomas, and two were T-cell large granular lymphocytic leukemia.
• Among the reported 536 second primary malignancies, the most frequent cancers were leukemias (333 reports, or 62%), followed by skin neoplasms (54 reports, or 10.1%), hematopoietic neoplasms excluding leukemias and lymphomas (26 reports, 4.85%), nervous system tumors (21 reports, 3.92%), and respiratory neoplasms (20 reports, 3.73%).

IN PRACTICE:

“We will continue to monitor the data released by the FDA to learn more about CAR T-associated risks. However, it’s crucial to stress that the benefits of CAR T-cell therapies still outweigh the risks for the approved indications,” Magdi Elsallab, MD, the study’s co-lead author, said in a news release.

SOURCE:

This work, led by Dr. Elsallab from Harvard Medical School in Boston, was published online on March 14 in Blood.

LIMITATIONS:

The limitations of the analysis include the presence of duplicate report submissions, incomplete data, difficulty establishing causal relationships, and the potential for both underreporting and overreporting based on the severity of adverse events. Furthermore, without the total number of prescribed products, it was difficult to determine the adverse event frequency.

DISCLOSURES:

The study funding source was not disclosed. Some of the authors reported financial ties with various organizations outside this work, including Bristol Myers Squibb, Janssen Biotech, Johnson & Johnson, Kite Pharma, and Novartis.
 

A version of this article appeared on Medscape.com.

TOPLINE:

Secondary cancers were flagged in 4.3% of all adverse event reports among patients who received CAR T therapy, with T-cell malignancies comprising only 0.15% of the total reports and 3.54% of all second primary malignancies, according to an analysis of adverse event reports submitted to the US Food and Drug Administration (FDA).

METHODOLOGY:

• In November 2023, the FDA announced its investigation into whether chimeric antigen receptor (CAR) T-cell immunotherapies can cause secondary blood cancers, specifically T-cell malignancies. At the time, the agency said: “Although the overall benefits of these products continue to outweigh their potential risks for their approved uses, FDA is investigating the identified risk of T-cell malignancy with serious outcomes.”
• In January 2024, the FDA issued boxed warnings on the six approved CART cell therapies, citing the possibility of second primary malignancies, including CAR-positive lymphomas, in patients who had received a CAR T agent.
• To evaluate the extent of these secondary cancers, researchers analyzed the FDA Adverse Event Reporting System database for CAR T-cell reports citing second primary malignancies.

TAKEAWAY:

• Overall, the authors identified 12,394 unique adverse events associated with CAR T therapy; of these, 536 adverse events (4.3%) were second primary malignancies.
• Axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tis-cel) accounted for most of the second primary malignancies reports — 51.7% (277 of 536 patients) for axi-cel and 33% (177 of 536 patients) for tis-cel.
• The researchers identified 19 cases of T-cell malignancies, representing only 0.15% of all unique adverse events and 3.54% of all second primary malignancies (19 of 536 patients); 17 of these cases were T-cell non-Hodgkin lymphomas, and two were T-cell large granular lymphocytic leukemia.
• Among the reported 536 second primary malignancies, the most frequent cancers were leukemias (333 reports, or 62%), followed by skin neoplasms (54 reports, or 10.1%), hematopoietic neoplasms excluding leukemias and lymphomas (26 reports, 4.85%), nervous system tumors (21 reports, 3.92%), and respiratory neoplasms (20 reports, 3.73%).

IN PRACTICE:

“We will continue to monitor the data released by the FDA to learn more about CAR T-associated risks. However, it’s crucial to stress that the benefits of CAR T-cell therapies still outweigh the risks for the approved indications,” Magdi Elsallab, MD, the study’s co-lead author, said in a news release.

SOURCE:

This work, led by Dr. Elsallab from Harvard Medical School in Boston, was published online on March 14 in Blood.

LIMITATIONS:

The limitations of the analysis include the presence of duplicate report submissions, incomplete data, difficulty establishing causal relationships, and the potential for both underreporting and overreporting based on the severity of adverse events. Furthermore, without the total number of prescribed products, it was difficult to determine the adverse event frequency.

DISCLOSURES:

The study funding source was not disclosed. Some of the authors reported financial ties with various organizations outside this work, including Bristol Myers Squibb, Janssen Biotech, Johnson & Johnson, Kite Pharma, and Novartis.
 

A version of this article appeared on Medscape.com.

TOPLINE:

Secondary cancers were flagged in 4.3% of all adverse event reports among patients who received CAR T therapy, with T-cell malignancies comprising only 0.15% of the total reports and 3.54% of all second primary malignancies, according to an analysis of adverse event reports submitted to the US Food and Drug Administration (FDA).

METHODOLOGY:

• In November 2023, the FDA announced its investigation into whether chimeric antigen receptor (CAR) T-cell immunotherapies can cause secondary blood cancers, specifically T-cell malignancies. At the time, the agency said: “Although the overall benefits of these products continue to outweigh their potential risks for their approved uses, FDA is investigating the identified risk of T-cell malignancy with serious outcomes.”
• In January 2024, the FDA issued boxed warnings on the six approved CART cell therapies, citing the possibility of second primary malignancies, including CAR-positive lymphomas, in patients who had received a CAR T agent.
• To evaluate the extent of these secondary cancers, researchers analyzed the FDA Adverse Event Reporting System database for CAR T-cell reports citing second primary malignancies.

TAKEAWAY:

• Overall, the authors identified 12,394 unique adverse events associated with CAR T therapy; of these, 536 adverse events (4.3%) were second primary malignancies.
• Axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tis-cel) accounted for most of the second primary malignancies reports — 51.7% (277 of 536 patients) for axi-cel and 33% (177 of 536 patients) for tis-cel.
• The researchers identified 19 cases of T-cell malignancies, representing only 0.15% of all unique adverse events and 3.54% of all second primary malignancies (19 of 536 patients); 17 of these cases were T-cell non-Hodgkin lymphomas, and two were T-cell large granular lymphocytic leukemia.
• Among the reported 536 second primary malignancies, the most frequent cancers were leukemias (333 reports, or 62%), followed by skin neoplasms (54 reports, or 10.1%), hematopoietic neoplasms excluding leukemias and lymphomas (26 reports, 4.85%), nervous system tumors (21 reports, 3.92%), and respiratory neoplasms (20 reports, 3.73%).

IN PRACTICE:

“We will continue to monitor the data released by the FDA to learn more about CAR T-associated risks. However, it’s crucial to stress that the benefits of CAR T-cell therapies still outweigh the risks for the approved indications,” Magdi Elsallab, MD, the study’s co-lead author, said in a news release.

SOURCE:

This work, led by Dr. Elsallab from Harvard Medical School in Boston, was published online on March 14 in Blood.

LIMITATIONS:

The limitations of the analysis include the presence of duplicate report submissions, incomplete data, difficulty establishing causal relationships, and the potential for both underreporting and overreporting based on the severity of adverse events. Furthermore, without the total number of prescribed products, it was difficult to determine the adverse event frequency.

DISCLOSURES:

The study funding source was not disclosed. Some of the authors reported financial ties with various organizations outside this work, including Bristol Myers Squibb, Janssen Biotech, Johnson & Johnson, Kite Pharma, and Novartis.
 

A version of this article appeared on Medscape.com.

The US Food and Drug Administration has granted ponatinib (Iclusig, Takeda) accelerated approval for use with chemotherapy in adults with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL).

The approval makes the third-generation tyrosine kinase inhibitor (TKI) the first targeted treatment approved for upfront use in adults with Ph+ ALL, Takeda said in a press release.

Ponatinib was previously approved as monotherapy for Ph+ ALL when no other kinase inhibitors are indicated or for T315I-positive Ph+ ALL, as well as for chronic myeloid leukemia.

Approval for the new indication was based on the PhALLCON trial. In the trial, 245 patients were randomized 2:1 to either ponatinib 30 mg once daily or the first-generation TKI imatinib (Gleevec, Novartis) 600 mg once daily on a chemotherapy background consisting of three cycles of vincristine/dexamethasone induction, six cycles methotrexate/cytarabine consolidation, and 11 cycles of vincristine/prednisone maintenance.

At the end of induction, 12% of patients in the imatinib arm vs 30% in the ponatinib group were in complete remission with no minimal residual disease. Event-free survival data are not yet mature.

At the 2023 American Society of Clinical Oncology annual meeting, an investigator on the trial said that ponatinib plus low-intensity chemotherapy has the potential to become the new standard of care for upfront Ph+ All. However, continued approval for the new indication may depend on trials confirming clinical benefit, Takeda said.

Ponatinib carries a boxed warning of arterial occlusive events, venous thromboembolic events, heart failure, and hepatotoxicity.

The most common adverse reactions reported in the PhALLCON trial were hepatic dysfunction, arthralgia, rash, headache, pyrexia, abdominal pain, constipation, fatigue, nausea, oral mucositis, hypertension, pancreatitis/elevated lipase, peripheral neuropathy, hemorrhage, febrile neutropenia, fluid retention and edema, vomiting, paresthesia, and cardiac arrhythmias.

The recommended ponatinib dose is 30 mg orally once daily until the end of induction, dropping down to 15 mg once daily in patients who go into remission with no minimal residual disease after induction, for up to 20 cycles or until loss of response or unacceptable toxicity.

Thirty tablets of 30 mg or 15 mg cost $21,944.54, according to Drugs.com. 
 

A version of this article appeared on Medscape.com.

The US Food and Drug Administration has granted ponatinib (Iclusig, Takeda) accelerated approval for use with chemotherapy in adults with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL).

The approval makes the third-generation tyrosine kinase inhibitor (TKI) the first targeted treatment approved for upfront use in adults with Ph+ ALL, Takeda said in a press release.

Ponatinib was previously approved as monotherapy for Ph+ ALL when no other kinase inhibitors are indicated or for T315I-positive Ph+ ALL, as well as for chronic myeloid leukemia.

Approval for the new indication was based on the PhALLCON trial. In the trial, 245 patients were randomized 2:1 to either ponatinib 30 mg once daily or the first-generation TKI imatinib (Gleevec, Novartis) 600 mg once daily on a chemotherapy background consisting of three cycles of vincristine/dexamethasone induction, six cycles methotrexate/cytarabine consolidation, and 11 cycles of vincristine/prednisone maintenance.

At the end of induction, 12% of patients in the imatinib arm vs 30% in the ponatinib group were in complete remission with no minimal residual disease. Event-free survival data are not yet mature.

At the 2023 American Society of Clinical Oncology annual meeting, an investigator on the trial said that ponatinib plus low-intensity chemotherapy has the potential to become the new standard of care for upfront Ph+ All. However, continued approval for the new indication may depend on trials confirming clinical benefit, Takeda said.

Ponatinib carries a boxed warning of arterial occlusive events, venous thromboembolic events, heart failure, and hepatotoxicity.

The most common adverse reactions reported in the PhALLCON trial were hepatic dysfunction, arthralgia, rash, headache, pyrexia, abdominal pain, constipation, fatigue, nausea, oral mucositis, hypertension, pancreatitis/elevated lipase, peripheral neuropathy, hemorrhage, febrile neutropenia, fluid retention and edema, vomiting, paresthesia, and cardiac arrhythmias.

The recommended ponatinib dose is 30 mg orally once daily until the end of induction, dropping down to 15 mg once daily in patients who go into remission with no minimal residual disease after induction, for up to 20 cycles or until loss of response or unacceptable toxicity.

Thirty tablets of 30 mg or 15 mg cost $21,944.54, according to Drugs.com. 
 

A version of this article appeared on Medscape.com.

The US Food and Drug Administration has granted ponatinib (Iclusig, Takeda) accelerated approval for use with chemotherapy in adults with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL).

The approval makes the third-generation tyrosine kinase inhibitor (TKI) the first targeted treatment approved for upfront use in adults with Ph+ ALL, Takeda said in a press release.

Ponatinib was previously approved as monotherapy for Ph+ ALL when no other kinase inhibitors are indicated or for T315I-positive Ph+ ALL, as well as for chronic myeloid leukemia.

Approval for the new indication was based on the PhALLCON trial. In the trial, 245 patients were randomized 2:1 to either ponatinib 30 mg once daily or the first-generation TKI imatinib (Gleevec, Novartis) 600 mg once daily on a chemotherapy background consisting of three cycles of vincristine/dexamethasone induction, six cycles methotrexate/cytarabine consolidation, and 11 cycles of vincristine/prednisone maintenance.

At the end of induction, 12% of patients in the imatinib arm vs 30% in the ponatinib group were in complete remission with no minimal residual disease. Event-free survival data are not yet mature.

At the 2023 American Society of Clinical Oncology annual meeting, an investigator on the trial said that ponatinib plus low-intensity chemotherapy has the potential to become the new standard of care for upfront Ph+ All. However, continued approval for the new indication may depend on trials confirming clinical benefit, Takeda said.

Ponatinib carries a boxed warning of arterial occlusive events, venous thromboembolic events, heart failure, and hepatotoxicity.

The most common adverse reactions reported in the PhALLCON trial were hepatic dysfunction, arthralgia, rash, headache, pyrexia, abdominal pain, constipation, fatigue, nausea, oral mucositis, hypertension, pancreatitis/elevated lipase, peripheral neuropathy, hemorrhage, febrile neutropenia, fluid retention and edema, vomiting, paresthesia, and cardiac arrhythmias.

The recommended ponatinib dose is 30 mg orally once daily until the end of induction, dropping down to 15 mg once daily in patients who go into remission with no minimal residual disease after induction, for up to 20 cycles or until loss of response or unacceptable toxicity.

Thirty tablets of 30 mg or 15 mg cost $21,944.54, according to Drugs.com. 
 

A version of this article appeared on Medscape.com.

SAN DIEGO — Transmasculine patients with acne require unique care that not only is sensitive but also reflects an understanding about factors that can affect their skin such as hormone therapy, a dermatologist told colleagues in a session at the American Academy of Dermatology annual meeting.

In these patients, treatment of acne is crucial, said Howa Yeung, MD, MSc, assistant professor of dermatology, Emory University, Atlanta. “These are patients who are suffering and reporting that they’re having mental health impacts” related to acne.

In transmasculine patients — those who were biologically female at birth but identify as masculine — testosterone therapy greatly boosts the risk for acne, even in adults who are long past adolescence, Dr. Yeung said. Data suggest that acne appears within the first 6 months after testosterone therapy begins, he said, “and the maximal and complete effect occurs within 1-2 years.”

A 2021 study tracked 988 transgender patients receiving testosterone at Fenway Health in Boston and found that 31% had a diagnosis of acne, up from 6.3% prior to taking hormones. And 2 years following the start of therapy, 25.1% had acne, with cases especially common among those aged 18-20.75 years (29.6%). Even among those aged 28.25-66.5 years, 17.1% had acne.

Transmasculine patients may develop acne in areas across the body “in places that you normally won’t see by just looking at the patient,” Dr. Yeung said. Excoriation in addition to comedones, papules, pustules, and nodules can be common, he added.

Dr. Yeung highlighted a 2019 study of transgender men that linked higher levels of acne to higher levels of serum testosterone, higher body mass index, and current smoking. And in a 2014 study, 6% of 50 transmasculine patients had moderate to severe acne after an average of 10 years on testosterone therapy.

A 2020 study of 696 transgender adults surveyed in California and Georgia found that 14% of transmasculine patients had moderate to severe acne — two thirds attributed it to hormone therapy — vs 1% of transfeminine patients, said Dr. Yeung, the lead author of the study. However, transmasculine patients were less likely to have seen a dermatologist.

Dr. Yeung also highlighted a 2021 study he coauthored that linked current moderate to severe acne in transmasculine patients taking testosterone to higher levels of depression and anxiety vs counterparts who had never had those forms of acne.

Another factor affecting acne in transmasculine patients is the use of chest binders to reduce breast size. “Wearing a chest binder is really helpful for a lot of our patients and is associated with improved self-esteem, mood, mental health, and safety in public,” Dr. Yeung said. However, the binders can contribute to skin problems.

Dr. Yeung said he and his colleagues emphasize the importance of breathable material in binders and suggest to patients that they not wear them when they’re in “safe spaces.”

Isotretinoin, Contraception Considerations

As for treatment of acne in transgender patients, Dr. Yeung cautioned colleagues to not automatically reject isotretinoin as an option for transgender patients who have a history of depression. Dermatologists may be tempted to avoid the drug in these patients because of its link to suicide, he said. (This apparent association has long been debated.) But, Dr. Yeung said, it’s important to consider that many of these patients suffered from anxiety and depression because of the lack of access to proper gender-reassignment treatment.

When using isotretinoin, he emphasized, it’s crucial to consider whether transmasculine patients could become pregnant while on this therapy. Consider whether the patient has the organs needed to become pregnant and ask questions about the potential that they could be impregnated.

“Remember that sexual behavior is different from gender identity,” Dr. Yeung said. A transmasculine person with a uterus and vagina, for example, may still have vaginal intercourse with males and potentially become pregnant. “So, we need to assess what kind of sexual behavior our patients are taking part in.”

Contraceptives such as intrauterine devices, implants, and injectable options may be helpful for transmasculine patients because they can reduce menstrual symptoms like spotting that can be distressing to them, he said. By helping a patient take a contraceptive, “you may actually be helping with their gender dysphoria and helping them get on isotretinoin.”

Dr. Yeung disclosed fees from JAMA and American Academy of Dermatology; grants/research funding from the American Acne & Rosacea Society, Dermatology Foundation, Department of Veterans Affairs, National Eczema Association, and National Institutes of Health; and speaker/faculty education honoraria from Dermatology Digest.

A version of this article appeared on Medscape.com.

SAN DIEGO — Transmasculine patients with acne require unique care that not only is sensitive but also reflects an understanding about factors that can affect their skin such as hormone therapy, a dermatologist told colleagues in a session at the American Academy of Dermatology annual meeting.

In these patients, treatment of acne is crucial, said Howa Yeung, MD, MSc, assistant professor of dermatology, Emory University, Atlanta. “These are patients who are suffering and reporting that they’re having mental health impacts” related to acne.

In transmasculine patients — those who were biologically female at birth but identify as masculine — testosterone therapy greatly boosts the risk for acne, even in adults who are long past adolescence, Dr. Yeung said. Data suggest that acne appears within the first 6 months after testosterone therapy begins, he said, “and the maximal and complete effect occurs within 1-2 years.”

A 2021 study tracked 988 transgender patients receiving testosterone at Fenway Health in Boston and found that 31% had a diagnosis of acne, up from 6.3% prior to taking hormones. And 2 years following the start of therapy, 25.1% had acne, with cases especially common among those aged 18-20.75 years (29.6%). Even among those aged 28.25-66.5 years, 17.1% had acne.

Transmasculine patients may develop acne in areas across the body “in places that you normally won’t see by just looking at the patient,” Dr. Yeung said. Excoriation in addition to comedones, papules, pustules, and nodules can be common, he added.

Dr. Yeung highlighted a 2019 study of transgender men that linked higher levels of acne to higher levels of serum testosterone, higher body mass index, and current smoking. And in a 2014 study, 6% of 50 transmasculine patients had moderate to severe acne after an average of 10 years on testosterone therapy.

A 2020 study of 696 transgender adults surveyed in California and Georgia found that 14% of transmasculine patients had moderate to severe acne — two thirds attributed it to hormone therapy — vs 1% of transfeminine patients, said Dr. Yeung, the lead author of the study. However, transmasculine patients were less likely to have seen a dermatologist.

Dr. Yeung also highlighted a 2021 study he coauthored that linked current moderate to severe acne in transmasculine patients taking testosterone to higher levels of depression and anxiety vs counterparts who had never had those forms of acne.

Another factor affecting acne in transmasculine patients is the use of chest binders to reduce breast size. “Wearing a chest binder is really helpful for a lot of our patients and is associated with improved self-esteem, mood, mental health, and safety in public,” Dr. Yeung said. However, the binders can contribute to skin problems.

Dr. Yeung said he and his colleagues emphasize the importance of breathable material in binders and suggest to patients that they not wear them when they’re in “safe spaces.”

Isotretinoin, Contraception Considerations

As for treatment of acne in transgender patients, Dr. Yeung cautioned colleagues to not automatically reject isotretinoin as an option for transgender patients who have a history of depression. Dermatologists may be tempted to avoid the drug in these patients because of its link to suicide, he said. (This apparent association has long been debated.) But, Dr. Yeung said, it’s important to consider that many of these patients suffered from anxiety and depression because of the lack of access to proper gender-reassignment treatment.

When using isotretinoin, he emphasized, it’s crucial to consider whether transmasculine patients could become pregnant while on this therapy. Consider whether the patient has the organs needed to become pregnant and ask questions about the potential that they could be impregnated.

“Remember that sexual behavior is different from gender identity,” Dr. Yeung said. A transmasculine person with a uterus and vagina, for example, may still have vaginal intercourse with males and potentially become pregnant. “So, we need to assess what kind of sexual behavior our patients are taking part in.”

Contraceptives such as intrauterine devices, implants, and injectable options may be helpful for transmasculine patients because they can reduce menstrual symptoms like spotting that can be distressing to them, he said. By helping a patient take a contraceptive, “you may actually be helping with their gender dysphoria and helping them get on isotretinoin.”

Dr. Yeung disclosed fees from JAMA and American Academy of Dermatology; grants/research funding from the American Acne & Rosacea Society, Dermatology Foundation, Department of Veterans Affairs, National Eczema Association, and National Institutes of Health; and speaker/faculty education honoraria from Dermatology Digest.

A version of this article appeared on Medscape.com.

SAN DIEGO — Transmasculine patients with acne require unique care that not only is sensitive but also reflects an understanding about factors that can affect their skin such as hormone therapy, a dermatologist told colleagues in a session at the American Academy of Dermatology annual meeting.

In these patients, treatment of acne is crucial, said Howa Yeung, MD, MSc, assistant professor of dermatology, Emory University, Atlanta. “These are patients who are suffering and reporting that they’re having mental health impacts” related to acne.

In transmasculine patients — those who were biologically female at birth but identify as masculine — testosterone therapy greatly boosts the risk for acne, even in adults who are long past adolescence, Dr. Yeung said. Data suggest that acne appears within the first 6 months after testosterone therapy begins, he said, “and the maximal and complete effect occurs within 1-2 years.”

A 2021 study tracked 988 transgender patients receiving testosterone at Fenway Health in Boston and found that 31% had a diagnosis of acne, up from 6.3% prior to taking hormones. And 2 years following the start of therapy, 25.1% had acne, with cases especially common among those aged 18-20.75 years (29.6%). Even among those aged 28.25-66.5 years, 17.1% had acne.

Transmasculine patients may develop acne in areas across the body “in places that you normally won’t see by just looking at the patient,” Dr. Yeung said. Excoriation in addition to comedones, papules, pustules, and nodules can be common, he added.

Dr. Yeung highlighted a 2019 study of transgender men that linked higher levels of acne to higher levels of serum testosterone, higher body mass index, and current smoking. And in a 2014 study, 6% of 50 transmasculine patients had moderate to severe acne after an average of 10 years on testosterone therapy.

A 2020 study of 696 transgender adults surveyed in California and Georgia found that 14% of transmasculine patients had moderate to severe acne — two thirds attributed it to hormone therapy — vs 1% of transfeminine patients, said Dr. Yeung, the lead author of the study. However, transmasculine patients were less likely to have seen a dermatologist.

Dr. Yeung also highlighted a 2021 study he coauthored that linked current moderate to severe acne in transmasculine patients taking testosterone to higher levels of depression and anxiety vs counterparts who had never had those forms of acne.

Another factor affecting acne in transmasculine patients is the use of chest binders to reduce breast size. “Wearing a chest binder is really helpful for a lot of our patients and is associated with improved self-esteem, mood, mental health, and safety in public,” Dr. Yeung said. However, the binders can contribute to skin problems.

Dr. Yeung said he and his colleagues emphasize the importance of breathable material in binders and suggest to patients that they not wear them when they’re in “safe spaces.”

Isotretinoin, Contraception Considerations

As for treatment of acne in transgender patients, Dr. Yeung cautioned colleagues to not automatically reject isotretinoin as an option for transgender patients who have a history of depression. Dermatologists may be tempted to avoid the drug in these patients because of its link to suicide, he said. (This apparent association has long been debated.) But, Dr. Yeung said, it’s important to consider that many of these patients suffered from anxiety and depression because of the lack of access to proper gender-reassignment treatment.

When using isotretinoin, he emphasized, it’s crucial to consider whether transmasculine patients could become pregnant while on this therapy. Consider whether the patient has the organs needed to become pregnant and ask questions about the potential that they could be impregnated.

“Remember that sexual behavior is different from gender identity,” Dr. Yeung said. A transmasculine person with a uterus and vagina, for example, may still have vaginal intercourse with males and potentially become pregnant. “So, we need to assess what kind of sexual behavior our patients are taking part in.”

Contraceptives such as intrauterine devices, implants, and injectable options may be helpful for transmasculine patients because they can reduce menstrual symptoms like spotting that can be distressing to them, he said. By helping a patient take a contraceptive, “you may actually be helping with their gender dysphoria and helping them get on isotretinoin.”

Dr. Yeung disclosed fees from JAMA and American Academy of Dermatology; grants/research funding from the American Acne & Rosacea Society, Dermatology Foundation, Department of Veterans Affairs, National Eczema Association, and National Institutes of Health; and speaker/faculty education honoraria from Dermatology Digest.

A version of this article appeared on Medscape.com.